Lactams as tachkinin antagonists

ABSTRACT

Compounds of the formula (I):  
                 
 
     or a pharmaceutically acceptable salt, prodrug, solvate or polymorph thereof, wherein R, R 1 , and Z are as defined herein, are useful in treating or preventing a condition for which an NK 2  antagonist is efficacious.

[0001] This invention relates to therapeutic agents of the lactam familyand to processes for the preparation of, intermediates used in thepreparation of, compositions containing and uses of, such derivatives.

[0002] International Patent Application Publication Number WO 96/05193discloses various (azetidin-1-ylalkyl)lactams as tachykinin antagonists.

[0003] International Patent Application Publication Number WO97/25322discloses various azetidinylalkyl derivatives of N-substituted nitrogenheterocycles as tachykinin antagonists.

[0004] The therapeutic agents of the present invention are antagonistsof tachykinins, including neurokinin A (NKA), neurokinin B (NKB) andSubstance P, acting at the human neurokinin-1 (NK₁), neurokinin-2 (NK₂)or neurokinin-3 (NK₃) receptor, or a combination of two or more thereof.They are therefore useful for preventing or treating inflammatorydisease, a central nervous system (CNS) disorder, a gastro-intestinal(GI) disorder, a disease caused by Helicobacter pylori or other ureasepositive Gram negative bacteria, urological conditions, a pulmonarydisorder, an allergy, a hypersensitivity disorder, a vasospasticdisease, a proliferative disorder, a fibrosing or collagen disease,reflux sympathetic dystrophy, an addiction disorder, a stress-relatedsomatic disorder, a peripheral neuropathy, a neuropathological disorder,a disorder related to immune enhancement or suppression, a rheumaticdisease, an opthalmic disease, acute and chronic pain or a viraldisease.

[0005] The present invention provides a compound of formula (I):

[0006] or a pharmaceutically acceptable salt, prodrug, solvate orpolymorph thereof, wherein:

[0007] R is het^(a);

[0008] R¹ is phenyl optionally substituted by one or more substituentsindependently selected from halogen, C₁₋₆ alkoxy optionally substitutedby one or more halogen, and C₁₋₆ alkyl optionally substituted by one ormore halogen;

[0009] m is 1-4;

[0010] Z is selected from:

[0011] a) N(R³)(R⁴X)

[0012] wherein X is NR³R⁵, OR³, Oaryl¹, Ohet^(b), Ohet^(c), aryl¹,het^(b) or het^(c);

[0013] b) N(R³)Y

[0014] wherein Y is aryl¹, het^(b) or het^(c); and

[0015] c) a 4-7 membered N containing saturated or partially saturatedheterocycle said heterocycle attached to the alkylene link via saidnitrogen atom, said heterocycle optionally containing an additional 1-3groups, each independently selected from C=O, NH, S(O)_(p) and 0;optionally, said heterocycle is:

[0016] i) spirofused with het^(b), such that both rings share 1 atom; or

[0017] ii) substituted by 1-3 groups each independently selected fromhet^(b), het^(c), aryl¹, R³, R⁴OR³, R⁴C(O)R³, OR³, OR⁷OR³, OR⁴OC(O)R³,OR⁴OC(O)NR³R⁶, S(O)_(p)R⁴, C(O)R³, C(O)NR³R⁶, C(O)OR³, R⁷C(O)OR³,C(O)R⁷OR³, C(O)OR⁷OR³, CF₃, NR³R⁶, R⁴NR³R⁵, OC(O)NR³R⁴ and NR³R⁵;

[0018] wherein R³ and R⁶ are both independently selected from H and C₁₋₆alkyl;

[0019] wherein R⁴ and R⁷ are both independently selected from C₁₋₆alkylene;

[0020] wherein R⁵ is selected from C(O)OR³, S(O)_(p)R³, S(O)_(p)aryl¹,C(O)R³, and C(O)NR³R⁶;

[0021] het^(b) is a 4-7 membered heterocycle containing 1-3 heteroatoms,each independently selected from N, O and S, said N being optionallysubstituted with O, said ring optionally containing 1-2 C═O groups, saidring being saturated or partially saturated, said ring being optionallybenzofused, said ring being optionally substituted by 1-3 substituentsselected from halo, R³, OR³, C(O)NR³R⁶, R⁷NR³R⁶, NR³R⁵, NHS(O)_(p)R⁴,S(O)_(p)NR³R⁶, S(O)_(p)R⁴, CN, NR³R⁶ and aryl¹;

[0022] het^(a) and het^(c) independently represent a 5-7 memberedaromatic heterocycle containing 1-3 heteroatoms each independentlyselected from N, O and S, said ring being optionally benzofused, saidring system as a whole being optionally substituted by 1-3 substituents,each independently selected from: halo, R³, OR³, C(O)NR³R⁶, R⁴NR³R⁶,NR³R⁵, NHS(O)_(p)R⁴, S(O)_(p)NR³R⁶, S(O)_(p)R⁴, CN, NR³R⁶, andR⁴NR³S(O)_(p)R³;

[0023] aryl¹ is phenyl or naphthyl, each optionally substituted by 1-3substituents, each independently selected from: halo, R³, OR³,C(O)NR³R⁶, R⁷NR³R⁶, NR³R⁵, NHS(O)_(p)R⁴, S(O)_(p)NR³R⁶, S(O)_(p)R⁴, CN;

[0024] p is 0, 1 or 2; and

[0025] n is 0-4.

[0026] Halo includes fluoro, chloro, bromo and iodo groups.

[0027] Alkyl and alkylene include both straight chain and branchedchain.

[0028] A pharmaceutically acceptable salt of a compound of the formula(I) may be readily prepared by mixing together solutions of a compoundof the formula (I) and the desired acid or base, as appropriate. Thesalt may precipitate from solution and be collected by filtration or maybe recovered by evaporation of the solvent.

[0029] The pharmaceutically acceptable salts of the compounds of theformula (I) include the acid addition and the base salts thereof.

[0030] Suitable acid addition salts are formed from acids which formnon-toxic salts and examples are the hydrochloride, hydrobromide,hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate,gluconate, succinate, saccharate, benzoate, methanesulphonate,ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoatesalts.

[0031] Suitable base salts are formed from bases which form non-toxicsalts and examples are the sodium, potassium, aluminium, calcium,magnesium, zinc and diethanolamine salts.

[0032] For a review on suitable salts see Berge et al, J. Pharm. Sci.,66, 1-19, 1977.

[0033] The pharmaceutically acceptable solvates of the compounds of theformula (I) include the hydrates thereof.

[0034] Also included within the present scope of the compounds of theformula (I) are polymorphs thereof.

[0035] It will also be appreciated that the compounds of the inventionwill include prodrugs of (I) and pharmaceutically acceptable derivativesof (I) in which the functional groups explicitly recited above have beenderivatised to provide prodrugs which can be converted to the parentcompound in vivo. Such prodrugs are discussed in Drugs of Today, 1983,19, 499-538 and Annual Reports in Medicinal Chemistry, 1975, Vol.10, Ch31, 306-326.

[0036] A compound of the formula (I) contains one or more asymmetriccarbon atoms and therefore exists in two or more stereoisomeric forms.Where a compound of the formula (I) contains an alkenyl or alkenylenegroup, cis (E) and trans (Z) isomerism may also occur. The presentinvention includes the individual stereoisomers of the compounds of theformula (I) and, where appropriate, the individual tautomeric formsthereof, together with mixtures thereof.

[0037] Those compounds of formula (I), which have the stereochemistryshown below are particularly preferred.

[0038] Separation of diastereoisomers or cis and trans isomers may beachieved by conventional techniques, e.g. by fractional crystallisation,chromatography or H.P.L.C. of a stereoisomeric mixture of a compound ofthe formula (I) or a suitable salt or derivative thereof. An individualenantiomer of a compound of the formula (I) may also be prepared from acorresponding optically pure intermediate or by resolution, such as byH.P.L.C. of the corresponding racemate using a suitable chiral supportor by fractional crystallisation of the diastereoisomeric salts formedby reaction of the corresponding racemate with a suitable opticallyactive acid or base, as appropriate.

[0039] Preferred embodiments of the present invention include compoundsof formula (I) wherein:

[0040] Preferably R is pyridyl, optionally substituted by NR³R⁶, R³ orOR³.

[0041] More preferably R is pyridyl, optionally substituted by NMe₂,C₁₋₂ alkyl or OC₁₋₂ alkyl.

[0042] Yet more preferably R is pyridyl optionally substituted by methylor ethyl.

[0043] Most preferably R is pyridyl optionally substituted by methyl.

[0044] Preferably the pyridyl moiety is substituted at the 2 position.

[0045] Preferably the lactam is attached to the pyridyl moiety at the 6position of the pyridyl group.

[0046] Preferably R¹ is phenyl optionally substituted by 1 or 2 halosubstituents.

[0047] More preferably R¹ is phenyl, optionally substituted by 1 or 2substituents selected from fluoro and chloro.

[0048] Yet more preferably R¹ is phenyl, 3,4-difluorophenyl,3-chlorophenyl, 4-chlorophenyl or 3,4-dichlorophenyl.

[0049] Most preferably R¹ is 3,4-difluorophenyl, 4-chlorophenyl or3,4-dichlorophenyl.

[0050] Most preferably R¹ is 3,4-dichlorophenyl.

[0051] Preferably m is 2-3

[0052] Most preferably m is 2.

[0053] Preferably n is 1-4.

[0054] More preferably n is 1-3.

[0055] Yet more preferably n is 1-2.

[0056] Most preferably n is 2.

[0057] Preferably R³ is H or C₁₋₄ alkyl; or

[0058] More preferably R³ is H or C₁₋₂ alkyl

[0059] Preferably R⁴ is C₁₋₄ alkylene

[0060] More preferably R⁴ is C₁₋₂ alkylene

[0061] Preferably R⁵ is C(O)OR³, C(O)R³, C(O)NR³R⁶

[0062] Preferably R⁶ is H, C₁₋₄ alkyl; or

[0063] More preferably R⁶ is H, C₁₋₂alkyl

[0064] Most preferably R⁶ is H

[0065] Preferably R⁷ is C₂₋₆ alkylene

[0066] More preferably R⁷ is C₂₋₄ alkylene

[0067] Preferably Z is a piperidine or azetidine group optionallysubstituted by one or more of het^(b) het^(c), aryl¹, OR³, R³ and NR³R⁵,wherein;

[0068] Het^(b) is a 5-6 membered saturated or partially saturatednitrogen containing heterocycle, said heterocycle optionallyincorporating 1-2 groups each independently selected from O, C═O and N,said heterocycle being optionally benzofused, said heterocycle beingoptionally substituted by 1-2 substituents, each independently selectedfrom OR³, R³, NR³R⁶, NR³R⁵, aryl¹, SO₂R⁴ and SO₂NR³R⁶;

[0069] Het^(c) is pyridyl, optionally substituted by 1 or 2 substituentseach independently selected from halo and OR³;

[0070] aryl¹ is phenyl, optionally substituted by 1 or 2 substituentseach independently selected from halo and OR³; and

[0071] R³, R⁴, R⁵ and R⁶ are as herein defined.

[0072] Preferably, the piperidine or aziridine group is substituted atthe 4 or 3 position respectively.

[0073] Most preferably Z is a piperidine or azetidine group, optionallysubstituted by het^(b), aryl¹ and NR³R⁵; wherein het^(b) is a morpholineor piperidine, optionally substituted at the 4 position by OH and ormethyl; wherein;

[0074] aryl¹ is phenyl optionally substituted by OH; and

[0075] R³ is H or methyl and R⁵ is C(O)CH₃.

[0076] Particularly preferred compounds include:

[0077](5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 131)

[0078](5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-hydroxypiperidinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 135a)

[0079](5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-methoxy-1-piperidinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone(Example 61)

[0080](5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{{2-[4-hydroxy-4-phenyl]-1-piperidinyl}ethyl}-2-piperidinone(Example 134)

[0081](5S)-5-(3,4-Dichlorophenyl)-5-{2-[4-hydroxy-4-(2-pyridyl)-1-piperidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone(Example 92)

[0082]N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-phenyl-4-piperidinyl)-acetamide(Example 90)

[0083](5S)-5-(3,4-Dichlorophenyl)-1-(6-methoxy-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 119)

[0084]5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-oxo-1-piperidinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 168)

[0085](5S)-5-(3,4-Dichlorophenyl)-5-{2-[3-(4-hydroxy-1-piperidinyl)-1-azetidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone(Example 73)

[0086]N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide(Example 158)

[0087] The invention further provides methods for the preparation of thecompounds of the invention, which are described below and in theexamples and Preparations section. The skilled man will appreciate thatthe compounds of the invention could be made by methods other than thoseherein described and or adaption of a plethora of methods known in theart. It is to be understood that the synthetic transformation methodsspecifically mentioned herein may be carried out in various differentsequences in order that the desired substances can be efficientlyassembled. The skilled chemist will exercise his judgement and skill asto the most efficient series of reactions for synthesis of a giventarget substance.

[0088] It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a substance of the invention. This may be achieved byconventional techniques, for example as described in “Protective Groupsin Organic Synthesis” by T. W. Greene and P. G. M. Wuts, John Wiley andSons Inc, 1991.

[0089] The compounds of formula (I) may be prepared in accordance withthe following scheme:

[0090] Compounds of formula (I) may be prepared from the compounds offormula (II) under the conditions of process step (a) a reductiveamination. This involves the reaction of amine Z-H with aldehyde (II),with a suitable metal hydride reducing agent (to reduce intermediateimine), optionally in the presence of a suitable base and/or acid,optionally in the presence of a Lewis acid catalyst, in a suitablesolvent at room temperature.

[0091] Suitable conditions include:

[0092] 1 eq aldehyde (or HCl salt of), 1-2 eq of amine, 1-3 eq suitablereducing agent (e.g. NaCNBH₃, NaBH(OAc)₃), optionally in the presence ofa base (eg Hünigs, Et₃N), and/or an acid (eg AcOH), in a suitablesolvent (eg dichloromethane (DCM), or tetrahydrofuran (THF)) at frombetween 15 minutes and 72 hours.

[0093] Or

[0094] (under Lewis acid catalysis)-1 eq aldehyde, excess of amine, anexcess of reducing agent, in the presence of a base (eg Et₃N), in asuitable solvent (e.g. EtOH), using 10 eq of Lewis acid (eg Ti(OiPr)₄).

[0095] Particularly suitable are:

[0096] 1 eq aldehyde, 1 to 1.5 eq amine, 1 to 3 eq NaBH(OAc)₃,optionally in the presence of 1 to 12 eq Et₃N, and optionally in thepresence of 2 to 30 eq of ACOH, in DCM or THF for between 15 minutes and72 hours at rt.

[0097] Or

[0098] (under Lewis acid catalysis)-1 eq aldehyde, 1.1 eq amine, 1.5 eqNaBH(OAc)₃, in the presence of 2.5 eq Et₃N, in EtOH using 10 eq ofTi(OiPr)₄.

[0099] The compounds of formula (II) may be prepared in accordance withthe following scheme.

[0100] Compounds of formula (IV) may be prepared from the compounds offormula (III) under the conditions of process step (b), an alkylationreaction. Suitable conditions include using an excess of alkylatingagent; in a preferred embodiment the conditions include an excess of acompound of formula (V)

[0101] where L is halo, with an excess of suitable base (typically analkali metal salt), in a suitable solvent (eg ethylene glycol dimethylether (DME), 1-methyl-2-pyrrolidinone (NMP)), optionally in the presenceof a catalyst (e.g. CuI), at the reflux temp of the reaction for 1 to 24hours.

[0102] Preferably a class of alkylation reaction known as the Goldbergreaction is used. This comprises 1.5 to 3 eq alkylating agent, V, whereL is F, Cl or Br, 1.1 to 1.5 eq of K₂CO₃, or KOtBu in NMP or DME atreflux for 1 to 24 hours.

[0103] Compounds of formula (II) may be prepared from the compounds offormula (IV) under the conditions of process step (c), a dioxalanhydrolysis reaction. Suitable conditions include hydrolysis under acidicconditions, such as 2.5N HCl in THF at rt for 24 hours.

[0104] Process steps (b) and (c) may be carried out using “one pot”methodology without the isolation of compounds of formula (IV)

[0105] The compounds of formula (II) may also be prepared in accordancewith the following scheme:

[0106] Compounds of formula (VI) may be prepared from the compounds offormula (III) under the conditions of process step (d), a dioxalancleavage reaction. This is conducted under non-aqueous strongly acidicconditions, for example, Amberlyst® 15 resin in MeOH at rt for 18 hours.

[0107] Compounds of formula (II) may be prepared from the compounds offormula (VI) under the conditions of process step (e), an acetalhydrolysis reaction. Suitable conditions include hydrolysis under acidicconditions to give the aldehyde, for example 1.1-2.5N HCl in THF at rtfor 18-24 hours.

[0108] The compounds of formula (I) may also be prepared in accordancewith the following scheme:

[0109] Compounds of formula (VIII) may be prepared from the compounds offormula (VII) under the conditions of process step (a), a reductiveamination reaction as discussed earlier.

[0110] Compounds of formula (I) may be prepared from the compounds offormula (VIII) under the conditions of process step (b), an alkylationreaction as discussed earlier.

[0111] In addition to the process routes already described, compounds offormula (I) where Z is N(R³)(R⁴X), where R³ is C₁₋₆ alkyl, R⁴ is C₁₋₆alkylene and X is het^(b) or het^(c), may be prepared from thecorresponding compounds of formula (I) where R² is hydrogen, by processstep (a) a reductive amination reaction as discussed earlier.

[0112] All of the above reactions and the preparations of novel startingmaterials used in the preceding methods are conventional and appropriatereagents and reaction conditions for their performance or preparation aswell as procedures for isolating the desired products will be well-knownto those skilled in the art with reference to literature precedents andthe Examples and Preparations hereto.

[0113] The affinity of the compounds of formula (I), and their salts,for the human NK₂ receptor can be assessed in vitro by testing theirability to compete with [³H] or [¹²⁵I] NKA (neurokinin A) for binding tomembranes prepared from Chinese hamster ovary cells expressing thecloned human NK₂ receptor using a modification of the method describedin McLean, S. et al., J. Pharm. Exp. Ther., 267, 472-9 (1993). Themembranes are incubated (90 min, 25° C.) with [³H] or [¹²⁵I] NKA and arange of concentrations of the test compound. Non specific binding wasdetermined in the presence of 1 μM SR-48968(N-[(2S)-4-[4-(acetylamino)-4-phenyl-1-piperidinyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide).

[0114] All the compounds of the present invention (as exemplifiedherein) had a binding affinity for NK₂ receptors with Ki<1000 nM.

[0115] The binding Ki expressed in nM for selected compounds of thepresent invention are expressed below:

[0116](5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 131) Ki=3.8

[0117](5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-hydroxypiperidinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 135a) Ki=3.7

[0118](5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-methoxy-1-piperidinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone(Example 61) Ki=12

[0119](5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[4-hydroxy-4-phenyl]-1-piperidinyl}ethyl}-2-piperidinone(Example 134) Ki=1.9

[0120](5S)-5-(3,4-Dichlorophenyl)-5-{2-[4-hydroxy-4-(2-pyridyl)-1-piperidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone(Example 92) Ki=7

[0121]N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-phenyl-4-piperidinyl)-acetamide(Example 90) Ki=2.4

[0122](5S)-5-(3,4-Dichlorophenyl)-1-(6-methoxy-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 119) Ki=5.4

[0123]5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-oxo-1-piperidinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 168) Ki=2.6

[0124](5S)-5-(3,4-Dichlorophenyl)-5-{2-[3-(4-hydroxy-1-piperidinyl)-1-azetidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone(Example 73) Ki=2.2

[0125]N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide(Example 158) Ki=8

[0126] The NK₂ receptor antagonist activity of the compounds of formula(I), and their salts, can be assessed in vitro by testing their abilityto antagonise the contractile effects of the selective NK₂ receptoragonist [β Ala⁸] NKA₍₄₋₁₀₎ in human bladder tissue or in rabbitpulmonary artery using the method of Patacchini and Maggi, Eur. J.Pharm., 236, 31-37 (1993).

[0127] Those compounds of the present invention, with binding affinityKi<10 nM (using the modified method described in McLean, S. et al, J.Pharm. Exp. Ther., 267, 472-9 (1993)) were profiled using the method ofPatacchini. These especially preferred compounds had K_(b)<10 nM orpA₂>8.

[0128] The compounds of formula (I), and their salts, can be tested forNK₂ receptor antagonist activity, in vivo, by testing their ability toinhibit bronchoconstriction induced by [β Ala⁸] NKA₍₄₋₁₀₎ in theaneasthetised guinea pig using the method described by Murai et al, J.Pharm. Exp. Ther., 262, 403-8 (1992) or Metcalfe et al, Br. J.Pharmacol., 112, 563P (1994).

[0129] The compounds of formula (I), and their salts, can be tested forNK₃ receptor antagonist activity, in vitro, by testing their ability tocompete with [³H] senktide (a selective NK₃ receptor agonist) onmembranes prepared from guinea pig cortex, using the method described inChretein, et al, Eur. J. Pharmacol, 256, 73-78 (1994).

[0130] The compounds of the present invention have been found to bepotent NK₂ antagonists.

[0131] The present invention provides for the use of a compound offormula (I) or a pharmaceutically acceptable salt, solvate or prodrugthereof as a medicament.

[0132] It further provides the use of compounds of formula (I) or apharmaceutically acceptable salt, solvate or prodrug thereof in thepreparation of a medicament for the treatment of a condition for whichan NK₂ antagonist is efficacious.

[0133] As NK₂ antagonists, the therapeutic agents of the presentinvention are therefore useful for preventing or treating aninflammatory disease such as arthritis, psoriasis, asthma orinflammatory bowel disease, a central nervous system (CNS) disorder suchas anxiety, depression, dementia or psychosis, a gastro-intestinal (GI)disorder such as functional bowel disease, dyspepsia, irritable bowelsyndrome, gastro-oesophageal reflux, faecal incontinence, colitis,ulcerative colitis or Crohn's disease, a disease caused by Helicobacterpylori or other urease positive Gram negative bacteria, urologicalconditions, ie a bladder disorder or a urogenital tract disorder (suchas incontinence, hyperreflexia, impotence or cystitis) or associatedconditions such as benign prostatic hyperplasia, over active bladder andlower uterine tract symptoms, a pulmonary disorder such as chronicobstructive airways disease, an allergy such as eczema, contactdermatitis, atopic dermatitis, urticaria, eczematoid dermatitis orrhinitis, a hypersensitivity disorder such as to poison ivy, avasospastic disease such as angina or Reynaud's disease, a proliferativedisorder such as cancer or a disorder involving fibroblastproliferation, a fibrosing or collagen disease such as scieroderma oreosinophillic fascioliasis, reflux sympathetic dystrophy such asshoulder/hand syndrome, an addiction disorder such as alcoholism, astress-related somatic disorder, a neuropathological disorder such asParkinson's disease, Alzheimer's disease or multiple sclerosis, adisorder related to immune enhancement or suppression such as systemiclupus erythematosis, a rheumatic disease such as fibrositis, emesis,cough, migraine, an opthalmic disease such as proliferative retinopathy,occular inflammation, conjunctivitis, or a viral disease such asinfluenza or a cold.

[0134] The compounds of the present invention are also useful in theprevention and treatment of pain; both acute and chronic.

[0135] Acute pain is short-lived (e.g. post-operative pain). Chronicpain is usually defined as pain persisting from 3 to 6 months andincludes somatogenic pains and psychogenic pains. Psychogenic pain isthat which occurs without an organic origin such as low back pain, atypical facial pain and chronic headache.

[0136] Other types of pain are caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation and vasculitis.Neuropathic pain is also caused by nerve damage from chronic alcoholism,human immunodeficiency virus infection, hypothyroidism, uremia orvitamin deficiencies.

[0137] Further types of pain are: neuropathic pain for example, AIDSneuropathy, post herpetic neuralgia, diabetic neuropathy and trigeminalneuralgia, fibromyalgia, pain associated with somatoform disorders,arthritic pain, cancer pain, neck pain, shoulder pain, back pain,cluster headaches, tension-type headache, migraine, herpes neuralgia,phantom limb pain, central pain, dental pain, NSAID-resistant pain,visceral pain, surgical pain, post-operative pain, bone injury pain,pain during labor and delivery, pain resulting from burns, includingsunburn, post-partum pain, angina pain, and genitourinary tract-relatedpain including cystitis. The term pain shall also preferably refer tonociceptive pain or nociception. Examples of acute pain include, inparticular, post-operative pain such as pain following a dentalextraction, migraine, headache and trigeminal neuralgia.

[0138] Examples of chronic pain include, in particular, musculoskeletalpain or pain associated with musculo-skeletal disorders such asrheumatoid arthritis, osteoarthritis, ankylosing spondylitis,sero-negative (non-rheumatoid) arthropathies, non-articular rheumatismand peri-articular disorders, and pain associated with cancer; pain withan inflammatory component such as rheumatic pain, secondary inflammatoryosteoarthrosis, dental pain and dysmenorrhoea; back pain such as lowback pain e.g. spinal stenosis, prolapsed disc or sciatica; trauma;herpes zoster; neuropathic pain such as post-herpetic neuralgia,trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia,causalgia, peripheral neuropathy, diabetic neuropathy,chemotherapy-induced neuropathy, AIDS related neuropathy, occipitalneuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflexsympathetic dystrophy, phantom limb pain; gastrointestinal pain such asfunctional bowel disorders, which include non-ulcer dyspepsia,non-cardiac chest pain and irritable bowel syndrome. (Irritable bowelsyndrome is a gastrointestinal disorder characterised by the presence ofabdominal pain and altered bowel habits without any evidence of organicdisease); traumatic pain such as postoperative pain; traumatic avulsionpain such as brachial plexus; chronic pain such as arthritic pain suchas occurring in osteo-, rheumatoid or psoriatic arthritis; various formsof headache such as migraine, acute or chronic tension headache,temporomandibular pain, maxillary sinus pain, cluster headache;odontalgia; pain of visceral origin; nerve entrapment pain; sport'sinjury pain; menstrual pain; meningitis; arachnoiditis: angina; gout;burns; scar pain; itch; and thalamic pain such as post stroke thalamicpain.

[0139] Accordingly the present invention provides the use of compoundsof formula (I) or a pharmaceutically acceptable salt, solvate or prodrugthereof in the preparation of a medicament for the treatment of acondition selected from: inflammatory disease, a central nervous system(CNS) disorder, a gastro-intestinal (GI) disorder, a disease caused byHelicobacter pylori or other urease positive Gram negative bacteria,urological conditions, a pulmonary disorder, an allergy, ahypersensitivity disorder, a vasospastic disease, a proliferativedisorder, a fibrosing or collagen disease, reflux sympathetic dystrophy,an addiction disorder, a stress-related somatic disorder, a peripheralneuropathy, a neuropathological disorder, a disorder related to immuneenhancement or suppression, a rheumatic disease, an opthalmic disease,acute and chronic pain or a viral disease.

[0140] A preferred embodiment of the present invention provides the useof compounds of formula (I) or a pharmaceutically acceptable salt,solvate or prodrug thereof in the preparation of a medicament for thetreatment of a condition selected from: urological conditions or acuteand chronic pain.

[0141] Particularly suitable urological conditions include incontinence,hyperreflexia, benign prostatic hyperplasia, over active bladder andlower uterine tract symptoms.

[0142] A particularly preferred urological condition is over activebladder.

[0143] A particularly preferred pain condition is neuropathic pain.

[0144] The invention also provides for a method of treating orpreventing a condition for which an NK₂ antagonist is efficacious whichcomprises administering a therapeutically effective amount of a compoundof formula (I) and pharmaceutically acceptable salts and prodrugsthereof to a patient in need of treatment.

[0145] The compounds of the formula (I) can also be administered incombination with other active agents. Preferred agents include:compounds which modulate the action of atrial natriuretic factor (alsoknown as atrial natriuretic peptide), such as inhibitors of neutralendopeptidase; compounds which inhibit angiotensin-converting enzymesuch as enalapril, and combined inhibitors of angiotensin-convertingenzyme and neutral endopeptidase such as omapatrilat; angiotensinreceptor antagonists such as losartan; substrates for NO-synthase, i.e.L-arginine; calcium-channel blockers such as amlodipine; antagonists ofendothelin receptors and inhibitors of endothelin-converting enzyme;cholesterol lowering agents e.g. statins and fibrates; antiplatelet andantithrombotic agents, e.g. tPA, uPA, warfarin, hirudin and otherthrombin inhibitors, heparin, thromboplastin activating factorinhibitors; insulin sensitising agents such as rezulin and hypoglycaemicagents such as glipizide; L-DOPA and carbidopa; acetylcholinesteraseinhibitors such as donezipil or steroidal; non-steroidalanti-inflammatory agents (NSAIDS) such as aspirin and ibuprofen; cGMPPDE₅ inhibitors such as sildenafil (Viagra™), vardenafil and cialis;muscarinic antagonists such as oxybutynin, tolterodine, propiverine,trospium chloride and darifenacin; alpha-adrenoceptor antagonists suchas doxazosin (Cardura™), tamsulosin,4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazolineand5-cyclopropyl-7-methoxy-2-(2-(4-morpholinylmethyl)-7,8-dihydro[1,6]naphthryridin-6(5H)-yl)-4(3H)-quinazolinone;serotonin/noradrenalin reuptake inhibitors (SNRI) such a duloxetine,venlafaxine and milnacipran; noradrenalin reuptake inhibitors such asreboxetine; NK₁ antagonists such as (αR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-Triazol-3-one(MK-869), lanepitant, dapitant and3-[[2-Methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine,(2S, 3S); 5-HT_(1A) agonists/antagonists such as buspirone androbalzotan; COX₂ inhibitors such as celecoxib (Celebrix™), rofecoxib(Vioxx™) and valdecoxib; non-selective COX inhibitors (preferably with‘GI protection’) such as HCT-1026 (nitroflurbiprofen); opioids such asmorphine, codeine; tricyclic antidepressants such as desipramine andamytriptiline; anticonvulsants such as gabapentin, serotonin reuptakeinhibitors such as fluoxetine and sertraline; serotonin receptoragonists and antagonists, cholinergic (muscarinic and nicotinic)analgesics, sedatives such as amobarbital and temazepam, skeletal musclerelaxants such as baclofen; NMDA receptor antagonists such asdextromorphan and ketamine; vanilloid receptor agonists such asresinferatoxin; HMG-CoA reductase inhibitors such as atorvastatin(Lipitor™), simvastatin (Zocor™), pravastatin (Pravacol™) androsuvastatin (Crestor™); and estrogenic modulators such as hormonereplacement therapy and selective estrogen receptor modulators, such aslasofoxifene, tamoxifene and raloxifene.

[0146] The NK₂ antagonists of this invention can also be administered incombination with other active agents in the treatment of urologicalconditions, particularly incontinence, hyperreflexia, benign prostatichyperplasia, over active bladder and lower uterine tract symptoms.

[0147] Accordingly the present invention provides for the use of acompound of formula (I) in the preparation of a medicament incombination with an agent selected from: Muscarinic antagonists;alpha-adrenoceptor antagonists; serotonin/noradrenalin reuptakeinhibitors (SNRI); noradrenalin reuptake inhibitors; NK₁ antagonists;5-HT_(1A) agonists/antagonists; PDE₅ inhibitors; COX₂ inhibitors;non-selective COX inhibitors; vanilloid receptor agonists; HMG-COAreductase inhibitors; and estrogenic modulators and selective estrogenreceptor modulators for the treatment of urological conditions.

[0148] The NK₂ antagonists of this invention can also be administered incombination with other active agents in the treatment of pain.

[0149] Accordingly the present invention provides for the use of acompound of formula (I) in the preparation of a medicament incombination with an agent selected from: NSAIDs, opioids, muscarinicantagonists; cholinergic analgesics; alpha-adrenoceptor antagonists;serotonin/noradrenalin reuptake inhibitors (SNRI); COX₂ inhibitors;non-selective COX inhibitors; tricyclic antidepressants,anticonvulsants, serotonin reuptake inhibitors, serotonin receptoragonists and antagonists, sedatives, skeletal muscle relaxant and NMDAreceptor antagonists for the treatment of pain.

[0150] It is to be appreciated that all references herein to treatmentinclude curative, palliative and prophylactic treatment.

[0151] The compounds of the formula (I) can be administered alone butwill generally be administered in admixture with a suitablepharmaceutical excipient, diluent or carrier selected with regard to theintended route of administration and standard pharmaceutical practice.

[0152] The present invention provides for a composition comprising acompound of formula (I) or a pharmaceutically acceptable salt, solvateor prodrug thereof and a pharmaceutically acceptable diluent or carrier.

[0153] The compounds of formula (I) may also be administered incombination with other suitable therapeutic agents. Accordingly thepresent invention provides for a composition comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate or prodrugthereof and an agent selected from: compounds which modulate the actionof atrial natriuretic factor (also known as atrial natriuretic peptide),such as inhibitors of neutral endopeptidase; compounds which inhibitangiotensin-converting enzyme, and combined inhibitors ofangiotensin-converting enzyme and neutral endopeptidase; angiotensinreceptor antagonists; substrates for NO-synthase; calcium-channelblockers; antagonists of endothelin receptors and inhibitors ofendothelin-converting enzyme-cholesterol lowering agents; antiplateletand antithrombotic agents, thromboplastin activating factor inhibitors;insulin sensitising agents and hypoglycaemic agents;acetylcholinesterase inhibitors; non-steroidal anti-inflammatory agents(NSAIDs); cGMP PDE₅ inhibitors; muscarinic antagonists;alpha-adrenoceptor antagonists; serotonin/noradrenalin reuptakeinhibitors (SNRI); noradrenalin reuptake inhibitors; NK₁ antagonists;5-HT_(1A) agonists/antagonists; COX₂ inhibitors; non-selective COXinhibitors (preferably with ‘GI protection’); opioids; tricyclicantidepressants; anticonvulsants, serotonin reuptake inhibitors;serotonin receptor agonists and antagonists, cholinergic (muscarinic andnicotinic) analgesics, sedatives, skeletal muscle relaxants; NMDAreceptor antagonists; vanilloid receptor agonists; HMG-CoA reductaseinhibitors; estrogenic modulators and selective estrogen receptormodulators, and a pharmaceutically acceptable diluent or carrier.

[0154] In preferred embodiments the invention provides a compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt, solvate or prodrug thereof and an agent selected from: Muscarinicantagonists; alpha-adrenoceptor antagonists; serotonin/noradrenalinreuptake inhibitors (SNRI); reuptake inhibitors; NK₁ antagonists;5-HT_(1A) agonists/antagonists; PDE₅ inhibitors; COX₂ inhibitors;non-selective COX inhibitors (preferably with ‘GI protection’);vanilloid receptor agonists; HMG-CoA reductase inhibitors; estrogenicmodulators and selective estrogen receptor modulators, and apharmaceutically acceptable diluent or carrier.

[0155] Another preferred embodiment provides a composition comprising acompound of formula (I) or a pharmaceutically acceptable salt, solvateor prodrug thereof and an agent selected from: NSAIDs, opioids,muscarinic antagonists; cholinergic analgesics; alpha-adrenoceptorantagonists; serotonin/noradrenalin reuptake inhibitors (SNRI); COX₂inhibitors; non-selective COX inhibitors; tricyclic antidepressants,anticonvulsants, serotonin reuptake inhibitors, serotonin receptoragonists and antagonists, sedatives, skeletal muscle relaxant and NMDAreceptor antagonists, and a pharmaceutically acceptable diluent orcarrier.

[0156] Where other therapeutic agents are given in combination with thecompounds of formula (I) they may be administered separately,simultaneously or sequentially.

[0157] The present invention provides for:

[0158] a) a composition comprising a compound of formula (I) or apharmaceutically acceptable salt, solvate or prodrug thereof and apharmaceutically acceptable diluent or carrier;

[0159] b) a composition comprising an agent selected from: compoundswhich modulate the action of atrial natriuretic factor (also known asatrial natriuretic peptide), such as inhibitors of neutralendopeptidase; compounds which inhibit angiotensin-converting enzyme,and combined inhibitors of angiotensin-converting enzyme and neutralendopeptidase; angiotensin receptor antagonists; substrates forNO-synthase; calcium-channel blockers; antagonists of endothelinreceptors and inhibitors of endothelin-converting enzyme; cholesterollowering agents; antiplatelet and antithrombotic agents, thromboplastinactivating factor inhibitors; insulin sensitising agents andhypoglycaemic agents; acetylcholinesterase inhibitors; non-steroidalanti-inflammatory agents (NSAIDs); cGMP PDE₅ inhibitors; muscarinicantagonists; alpha-adrenoceptor antagonists; serotonin/noradrenalinreuptake inhibitors (SNRI); noradrenalin reuptake inhibitors; NK₁antagonists; 5-HT_(1A) agonists/antagonists; COX₂ inhibitors;non-selective COX inhibitors (preferably with ‘GI protection’); opioids;tricyclic antidepressants; anticonvulsants, serotonin reuptakeinhibitors; serotonin receptor agonists and antagonists, cholinergic(muscarinic and nicotinic) analgesics, sedatives, skeletal musclerelaxants; NMDA receptor antagonists; vanilloid receptor agonists;HMG-CoA reductase inhibitors; estrogenic modulators and selectiveestrogen receptor modulators, and a pharmaceutically acceptable diluentor carrier; and

[0160] c) a container.

[0161] The invention further provides in a preferred embodiment for:

[0162] a) a composition comprising a compound of formula (I) or apharmaceutically acceptable salt, solvate or prodrug thereof and apharmaceutically acceptable diluent or carrier; and

[0163] b) a composition comprising a compound of formula (I) or apharmaceutically acceptable salt, solvate or prodrug thereof and anagent selected from: muscarinic antagonists; alpha-adrenoceptorantagonists; serotonin/noradrenalin reuptake inhibitors (SNRI); reuptakeinhibitors; NK₁ antagonists; 5-HT_(1A) agonists/antagonists; PDE₅inhibitors; COX₂ inhibitors; non-selective COX inhibitors (preferablywith ‘GI protection’); vanilloid receptor agonists; HMG-COA reductaseinhibitors; estrogenic modulators and selective estrogen receptormodulators, and a pharmaceutically acceptable diluent or carrier; and

[0164] c) a container.

[0165] In a further preferred embodiment, the invention provides for:

[0166] a) a composition comprising a compound of formula (I) or apharmaceutically acceptable salt, solvate or prodrug thereof and apharmaceutically acceptable diluent or carrier; and

[0167] b) a composition comprising a compound of formula (I) or apharmaceutically acceptable salt, solvate or prodrug thereof and anagent selected from: NSAIDs, opioids, muscarinic antagonists;cholinergic analgesics; alpha-adrenoceptor antagonists;serotonin/noradrenalin reuptake inhibitors (SNRI); COX₂ inhibitors;non-selective COX inhibitors; tricyclic antidepressants,anticonvulsants, serotonin reuptake inhibitors, serotonin receptoragonists and antagonists, sedatives, skeletal muscle relaxant and NMDAreceptor antagonists, and a pharmaceutically acceptable diluent orcarrier; and

[0168] c) a container.

[0169] For example, the compounds of the formula (I) can be administeredorally, buccally or sublingually in the form of tablets, capsules,ovules, elixirs, solutions or suspensions, which may contain flavouringor colouring agents, for immediate-, delayed-, modified-, sustained-,pulsed- or controlled-release applications.

[0170] Such tablets may contain excipients such as microcrystallinecellulose, lactose, sodium citrate, calcium carbonate, dibasic calciumphosphate and glycine, disintegrants such as starch (preferably corn,potato or tapioca starch), sodium starch glycollate, croscarmellosesodium and certain complex silicates, and granulation binders such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included.

[0171] Solid compositions of a similar type may also be employed asfillers in gelatin capsules. Preferred excipients in this regard includelactose, starch, a cellulose, milk sugar or high molecular weightpolyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of the formula (I) may be combined with various sweetening orflavouring agents, colouring matter or dyes, with emulsifying and/orsuspending agents and with diluents such as water, ethanol, propyleneglycol and glycerin, and combinations thereof.

[0172] The compounds of the formula (I) can also be administeredparenterally, for example, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrally,intrasternally, intracranially, intramuscularly or subcutaneously, orthey may be administered by infusion techniques. For such parenteraladministration they are best used in the form of a sterile aqueoussolution which may contain other substances, for example, enough saltsor glucose to make the solution isotonic with blood. The aqueoussolutions should be suitably buffered (preferably to a pH of from 3 to9), if necessary. The preparation of suitable parenteral formulationsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well-known to those skilled in the art.

[0173] The compounds of formula (I) can also be administeredintranasally or by inhalation and are conveniently delivered in the formof a dry powder inhaler or an aerosol spray presentation from apressurised container, pump, spray, atomiser or nebuliser, with orwithout the use of a suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray, atomiser or nebulisermay contain a solution or suspension of the active compound, e.g. usinga mixture of ethanol and the propellant as the solvent, which mayadditionally contain a lubricant, e.g. sorbitan trioleate. Capsules andcartridges (made, for example, from gelatin) for use in an inhaler orinsufflator may be formulated to contain a powder mix of a compound ofthe formula (I) and a suitable powder base such as lactose or starch.

[0174] They may also be administered by the ocular route. For ophthalmicuse, the compounds can be formulated as micronised suspensions inisotonic, pH adjusted, sterile saline, or, preferably, as solutions inisotonic, pH adjusted, sterile saline, optionally in combination with apreservative such as a benzylalkonium chloride. Alternatively, they maybe formulated in an ointment such as petrolatum.

[0175] Alternatively, the compounds of the formula (I) can beadministered in the form of a suppository or pessary, or they may beapplied topically in the form of a gel, hydrogel, lotion, solution,cream, ointment or dusting powder. The compounds of the formula (I) mayalso be dermally or transdermally administered, for example, by the useof a skin patch. They may also be administered by the pulmonary orrectal routes.

[0176] For application topically to the skin, the compounds of theformula (I) can be formulated as a suitable ointment containing theactive compound suspended or dissolved in, for example, a mixture withone or more of the following: mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound,emulsifying wax and water. Alternatively, they can be formulated as asuitable lotion or cream, suspended or dissolved in, for example, amixture of one or more of the following: mineral oil, sorbitanmonostearate, a polyethylene glycol, liquid paraffin, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-octyidodecanol, benzyl alcohol andwater.

[0177] The compounds of the formula (I) may also be used in combinationwith a cyclodextrin. Cyclodextrins are known to form inclusion andnon-inclusion complexes with drug molecules. Formation of adrug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

[0178] The compounds of the invention may have the advantage that theyare more potent, have a longer duration of action, are more stable, havefewer side effects, are more selective (in particular for the NK₂receptor) and have improved cardiac safety, or have other more usefulproperties than the compounds of the prior art.

[0179] The following examples illustrate the preparation of thecompounds of the formula (I):

EXAMPLE 1(5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-hydroxy-1-piperidinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0180]

[0181] Sodium triacetoxyborohydride (262 mg, 1.24 mmol) was added to asolution of the aldehyde from preparation 11a (250 mg, 0.62 mmol) and4-hydroxypiperidine (90 mg, 0.9 mmol) in dichloromethane (100 ml), andthe reaction stirred at room temperature for 90 minutes. The mixture waswashed with water, dried (MgSO₄) and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of dichloromethane:methanol (100:0to 95:5) to afford the title compound as a white solid, 156 mg.

[0182]¹Hnmr (CDCl₃, 400 MHz) δ: 1.58 (m, 2H), 1.90-2.30 (m, 11H), 2.60(m, 2H), 2.75 (m, 2H), 3.75 (m, 1H), 3.96 (d, 1H), 4.60 (d, 1H), 7.14(m, 1H), 7.25 (m, 1H), 7.40 (d, 1H), 7.50 (s, 1H), 7.72 (s, 2H), 8.50(d, 1H).

[0183] LRMS: m/z (TSP⁺) 448.1, 450.1 [MH⁺]

[0184] Microanalysis found: C, 58.34; H, 6.15; N, 8.57.C₂₃H₂₇Cl₂N₃O₂;0.10CH₂Cl₂;1H₂O requires C, 58.42; H, 6.20; N, 8.85%.

EXAMPLES 2 TO 10

[0185] The following examples of general structure:

[0186] were prepared from the aldehyde hydrochloride from preparation11b and the appropriate amines, following a similar procedure to thatdescribed in example 1. Ex Yield No. R (%) Data  2^(1a)

58 yellow gum ¹Hnmr (CDCl₃, 400MHz) δ: 1.40(s, 9H), 1.80-2.60(m, 9H),3.16(m, 3H), 3.90(d, 1H), 4.58(d, 1H), 4.88(s, 1H), 7.14(m, 1H), 7.22(d,1H), 7.41(d, 1H), 7.48(d, 1H), 7.72(d, 2H), 8.50(d, 1H). LRMS: m/z(TSP⁺) 507.2, 509.2 [MH⁺]Microanalysis found: C, 57.11; H, 6.96; N,10.42. C₂₈H₃₂Cl₂N₄O₃; 0.05CH₂Cl₂; 1H₂O requires C, 56.91; H, 6.31; N, #10.60%.  3^(2b)

29 white solid ¹Hnmr (CDCl₃, 300MHz) δ: 1.64-1.96(m, 2H), 2.16(m, 2H),2.23-2.43(m, 7H), 2.60(m, 1H), 2.78(m, 2H), 2.97(m, 1H), 3.20(m, 4H),3.43(m, 2H), 3.92(d, 1H), 4.52(m, 3H), 7.19(m, 2H), 7.43(d, 1H), 7.47(s,1H), 7.74(m, 2H), 8.52(d, 1H). LRMS: m/z (TSP⁺) 488.8, 490.7[M—SO₂NH₂]⁺Microanalysis Found: C, 40.29; H, 5.77; N, 11.18.C₂₅H₃₂Cl₂N₆O₃S; # 3HCl; 4H₂O requires C, 40.09; H, 5.79; N, 11.22% 4^(1c)

66 ¹Hnmr (CDCl₃, 400MHz) δ: 1.50(bs, 3H), 1.80-2.35(m, 8H), 2.56(m, 1H),3.60(bs, 4H), 3.95(d, 1H), 4.60(d, 1H), 7.08(dd, 1H), 7.24(m, 1H),7.38(d, 1H), 7.44(d, 1H), 7.66(d, 2H), 8.45(d, 1H). Microanalysis,Found: C, 59.72; H, 5.71; N, 9.56. C₂₂H₂₅Cl₂N₃O₂; 0.1CH₂Cl₂; 1H₂O Calc.C, 59.70; H, 5.76; N, 9.45%.  5^(d)

38 yellow solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.28(s, 3H), 1.60(m, 2H),2.24(m, 10H), 2.55-2.82(m, 4H), 3.80(m, 1H), 3.94(d, 1H), 4.60(d, 1H),7.15(dd, 1H), 7.34(d, 1H), 7.44(d, 1H), 7.52(s, 1H), 7.74(d, 2H),8.48(d, 1H). LRMS: m/z (TSP⁺) 462.2, 464.2 [MH⁺]Microanalysis found: C,56.46; H, 6.51; N, 8.07. C₂₄H₂₉Cl₂N₃O₂; 0.5CH₂Cl₂; H₂O requires C, #56.28; H, 6.17; N, 8.04%.  6^(e)

57 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.62(m, 2H), 1.74(m, 2H), 1.90(m,4H), 2.01(m, 1H), 2.15(m, 2H), 2.30(m, 2H), 2.44(m, 1H), 2.54(m, 1H),2.62(d, 3H), 2.83(m, 2H), 4.00(d, 1H), 4.20(m, 1H), 4.65(d, 1H), 7.10(m,1H), 7.20(m, 1H), 7.30(d, 2H), 7.39(d, 1H), 7.46(s, 1H), 7.66(m, 2H),7.74(d, 2H), 8.45(d, 1H). LRMS: m/z (TSP⁺) 601.4 [M⁺]  7^(f)

39 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.18(t, 3H), 1.82-2.02(m, 4H),2.07-2.37(m, 7H), 2.58(m, 1H), 3.36(m, 4H), 3.90(d, 1H), 4.07(q, 2H),4.61(d, 1H), 7.10(dd, 1H), 7.19(d, 1H), 7.38(d, 1H), 7.43(s, 1H),7.67(m, 2H), 8.44(d, 1H). LRMS: m/z (TSP⁺) 505.3, 507.2[MH⁺]Microanalysis found: C, 58.64; H, 6.16; N, 10.52. C₂₅H₃₀Cl₂N₄O₃;0.45H₂O  8^(g)

4 white solid ¹Hnmr (CDCl₃, 300MHz) δ: 1.92(m, 4H), 2.10-2.40(m, 6H),2.50(s, 3H), 2.54-2.88(m, 8H), 3.92(d, 1H), 4.64(d, 1H), 7.16(m, 1H),7.20(d, 1H), 7.40(d, 1H), 7.46(s, 1H), 7.72(d, 2H), 8.48(d, 1H). LRMS:m/z (TSP⁺) 461.2, 463.2 [MH⁺]  9^(h)

19 ¹Hnmr (CDCl₃, 400MHz) δ: 1.78(m, 2H), 1.85(m, 2H), 2.18(m, 2H),2.24(m, 3H), 2.54(m, 5H), 2.77(s, 3H), 3.28(m, 2H), 3.35(m, 2H), 3.88(d,1H), 4.64(d, 1H), 7.12(m, 1H), 7.18(d, 1H), 7.38(d, 1H), 7.44(d, 1H),7.68(d, 2H), 8.46(d, 1H). LRMS: m/z (TSP⁺) 525.1, 527.1 [MH⁺] 10^(1i)

43 White solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.40(s, 9H), 1.70-2.60(m, 14H),3.40(bs, 4H), 3.90(d, 1H), 4.62(d, 1H), 7.12(m, 1H), 7.22(d, 1H),7.40(d, 1H), 7.44(s, 1H), 7.70(s, 2H), 8.44(d, 1H). LRMS: m/z (TSP⁺)547.2, 549.2 [MH⁺]Microanalysis found: C, 58.52; H, 6.32; N, 9.13.C₂₈H₃₆Cl₂N₄O₃; 0.2CH₂Cl₂; H₂O requires C, 58.15; H, 6.64; N, 9.62%.

EXAMPLES 11 TO 16

[0187] The following examples of general structure:

[0188] were prepared from the aldehyde from preparation 12a and theappropriate amines, following the procedure described in example 1.Exam- Yield ple R (%) Data 11^(a)

74 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.54(d, 2H), 1.84-2.30(m, 12H),2.50-2.74(m, 6H), 3.66(m, 1H), 3.94(d, 1H), 4.60(d, 1H), 7.00(d, 1H),7.24(d, 1H), 7.42(d, 2H), 7.62(m, 2H). LRMS: m/z (TSP⁺) 462.1, 464.1[MH⁺]Microanalysis found: C, 59.81; H, 6.34; N, 8.57.C₂₄H₂₉Cl₂N₃O₂.0.1CH₂Cl₂; 0.7H₂O requires C, 59.87; H, 6.38; N, 8.69%.12^(b)

64 yellow solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.20(s, 3H), 1.55(d, 2H),1.70-2.65(m, 18H), 3.90(d, 1H), 4.60(d, 1H), 7.00(d, 1H), 7.25(d, 1H),7.40(dd, 2H), 7.60(m, 2H). LRMS: m/z (TSP⁺) 476.2, 478.2[MH⁺]Microanalysis found: C, 59.36; H, 6.63; N, 8.08.C₂₅H₃₁Cl₂N₃O₂.0.05CH₂Cl₂; 1.3H₂O requires C, 59.68; H, 6.74; N, 8.34%.13^(c)

70 ¹Hnmr (CDCl₃, 400MHz) δ: 1.10(s, 6H), 1.22(m, 2H), 1.57-1.80(m, 6H),1.92(m, 3H), 2.10(m, 2H), 2.25(m, 2H), 2.50(m, 4H), 2.82(m, 2H), 4.88(d,1H), 4.50(d, 1H), 6.95(d, 1H), 7.20(d, 1H), 7.38(d, 2H), 7.56(m, 2H).LRMS: m/z (ES⁺) 504, 506 [MH⁺] 14^(d)

51 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.90-2.20(m, 12H), 2.30(m, 4H),2.52(s, 3H), 2.58(m, 2H), 2.70(d, 1H), 3.92(d, 1H), 4.65(d, 1H), 5.40(d,1H), 7.00(d, 1H), 7.18-7.36(m, 6H), 7.40(d, 2H), 7.60(dd, 2H). LRMS: m/z(TSP⁺) 580.2, 582.2 [MH⁺] 15^(e)

39 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.70(m, 3H), 1.95-2.05(m, 4H),2.18(m, 2H), 2.30(m, 5H), 2.54(s, 3H), 2.54(m, 1H), 2.65(m, 2H), 3.95(d,1H), 4.62(d, 1H), 7.00(m, 3H), 7.30(m, 1H), 7.40(dd, 4H), 7.60(dd, 2H).LRMS: m/z (ES⁺) 556, 558 [MH⁺]Microanalysis found: C, 63.60; H, 5.76; N,7.41. C₃₀H₃₂Cl₂FN₃O₂; 0.1CH₂Cl₂: 0.1H₂O requires C, # 63.78; H, 5.76; N,7.41%. 16^(f)

62 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.95-2.40(m, 11H), 2.58(s, 3H),2.58(m, 1H), 3.65(m, 4H), 3.90(d, 1H), 4.62(d, 1H), 7.00(d, 1H), 7.28(d,1H), 7.40(d, 2H), 7.60(dd, 2H). LRMS: m/z (TSP⁺) 448.2, 450.2[MH⁺]Microanalysis found: C, 60.64; H, 5.98; N, 9.16. C₂₃H₂₇Cl₂N₃O₂;0.1CH₂Cl₂ requires C, 60.73; H, 6.00; N, 9.20%.

EXAMPLE 17(5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-phenyl-1-piperidinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0189]

[0190] Sodium triacetoxyborohydride (267 mg, 1.26 mmol) was added to asolution of the aldehyde hydrochloride from preparation 11b (250 mg,0.63 mmol) and 4-phenylpiperidine (151 mg, 0.94 mmol) in dichloromethane(200 ml), and the reaction stirred at room temperature for 2 hours. Themixture was washed with 2N sodium hydroxide solution (200 ml), theaqueous layer extracted with dichloromethane (2×200 ml), the combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure. The crude product was purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) aseluant to afford the title compound as a white foam.

[0191]¹Hnmr (CDCl₃, 400 MHz) δ: 1.74 (m, 6H), 1.83-2.08 (m, 5H), 2.18(m, 2H), 2.32 (m, 2H), 2.40 (m, 1H), 2.60 (m, 1H), 3.90 (d, 1H), 4.68(d, 1H), 7.18 (m, 4H), 7.28 (m, 3H), 7.41 (d, 1H), 7.50 (s, 1H), 7.73(m, 2H), 8.50 (d, 1H).

[0192] Microanalysis found: C, 66.65; H, 6.16; N, 8.06.C₂₉H₃₁Cl₂N₃0;0.78H₂O requires C, 66.66; H, 6.28; N, 8.04%.

EXAMPLES 18 TO 25

[0193] The following examples of general structure:

[0194] were prepared from the aldehyde hydrochloride from preparation11b and the appropriate amine, following a similar procedure to thatdescribed in example 17. Yield Example R (%) Data 18^(1a)

50 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 2.24(m, 2H), 2.41-2.75(m, 5H),2.91(m, 1H), 3.80-4.00(m, 2H), 4.40(d, 1H), 4.54(d, 1H), 7.30(m, 4H),7.39(d, 1H), 7.43(s, 1H), 7.54(m, 3H), 7.88(d, 1H), 8.15(dd, 1H),8.61(d, 1H), 9.90(bs, 1H), 10.05(bs, 1H). LRMS: m/z (TSP⁺) 454.0, 456.0[MH⁺] 19^(1b)

65 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 2.25(m, 2H), 2.42(m, 1H),2.57(m, 3H), 2.75(m, 1H), 2.90(m, 1H), 3.01(m, 2H), 3.16(m, 2H), 4.35(m,2H), 4.58(d, 1H), 7.21(m, 5H), 7.38(d, 1H), 7.42(d, 2H), 7.50(s, 1H),7.84(d, 1H), 8.05(dd, 1H), 8.62(d, 1H), 9.82(bs, 1H), 9.96(bs, 1H).LRMS: m/z (TSP⁺) 468.0, 470.0 [MH⁺]Microanalysis found: C, 57.32; H,5.50; N, 7.59. # C₂₆H₂₇Cl₂N₃O; 2HCl; 0.05CH₂Cl₂requires C, 57.35; H,5.38; N, 7.70%. 20^(c)

69 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.63-1.88(m, 6H), 2.08-2.40(m,5H), 2.55-2.64(m, 1H), 2.89(m, 4H), 3.57(m, 4H), 3.93(d, 1H), 4.62(d,1H), 7.16(m, 1H), 7,23(d, 1H), 7.42(d, 1H), 7.48(s, 1H), 7.74(d, 2H),8.49(m, 1H). LRMS: m/z (TSP⁺) 473, 475 [MH⁺]Microanalysis found: C,62.66; H, 6.21; N, 8.80. C₂₅H₂₉Cl₂N₃O₂; 0.1CH₂Cl₂ requires C, # 62.43;H, 6.09; N, 8.70%. 21^(2d)

15 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.68(m, 2H), 1.91-2.16(m, 5H),2.16-2.24(m, 2H), 2.24-2.40(m, 4H), 2.53-2.73(m, 3H), 3.95(d, 1H),4.70(d, 1H), 7.14(m, 1H), 7.27(m, 2H), 7.36(m, 2H), 7.41(d, 1H), 7.45(d,2H), 7.50(s, 1H), 7.71(m, 2H), 8.48(d, 1H). LRMS: m/z (TSP⁺) 425.1,526.1 [MH⁺] 22^(3e)

64 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.38-1.78(m, 3H), 1.85-2.43(m,11H), 2.51-2.78(m, 3H), 3.98(d, 1H), 4.72(d, 1H), 7.02(m, 2H), 7.15(dd,1H), 7.25(d, 1H), 7.42(m, 3H), 7.51(s, 1H), 7.73(m, 2H), 8.48(d, 1H).LRMS: m/z (TSP⁺) 542.1, 544.1 [MH⁺]Microanalysis found: C, 63.55; H,5.87; N, 7.48. C₂₉H₃₀Cl₂FN₃O₂; 0.3H₂O requires C, 63.58; H, # 5.63; N,7.67%. 23^(f)

77 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 0.80(t, 3H), 1.42(m, 4H), 1.58(m,3H), 1.95-2.02(m, 3H), 2.17(m, 4H), 2.25(m, 2H), 2.50(m, 3H), 3.88(d,1H), 4.60(d, 1H), 7.10(dd, 1H), 7.18(d, 1H), 7.38(d, 1H), 7.42(s, 1H),7.64(m, 2H), 8.42(d, 1H). LRMS: m/z (TSP⁺) 476.2, 478.2 [MH⁺] 24^(g)

46 clear oil ¹Hnmr (CDCl₃, 400MHz) δ: 1.65(m, 2H), 1.82(m, 2H),1.92-2.36(m, 9H), 2.58(m, 1H), 2.63(m, 2H), 3.90(d, 1H), 4.60(d, 1H),4.98(s, 2H), 7.04(m, 1H), 7.14(m, 2H), 7.20(m, 3H), 7.39(d, 1H), 7.45(s,1H), 7.66(s, 2H), 8.45(d, 1H). LRMS: m/z (TSP⁺) 536.2, 538.2 [MH⁺]25^(h)

20 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.60(d, 2H), 1.99(m, 4H), 2.16(m,2H), 2.20-2.40(m, 5H), 2,58(m, 1H), 2.72(m, 2H), 3.95(d, 1H), 4.61(d,1H), 7.14(m, 1H), 7.21(m, 1H), 7.32(d, 1H), 7.40(d, 1H), 7.47(m, 2H),7.61(dd, 1H), 7.66(m, 2H), 7.81(d, 1H), 8.46(d, 1H). LRMS: m/z (TSP⁺)550.2, 552.2 [MH⁺]

EXAMPLES 26 TO 31

[0195] The following examples of general structure:

[0196] were prepared from the aldehyde hydrochloride from preparation12b and the appropriate amine, following the procedure described inexample 17. Yield Example R (%) Data 26^(a)

29 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.14(dq, 2H), 1.45(m, 2H),1.57(m, 1H), 1.63-1.82(m, 4H), 2.00-2.18(m, 2H), 2.18-2.34(m, 2H),2.56(m, 4H), 2.66(m, 2H), 3.26(m, 4H), 3.85(d, 1H), 3.94(m, 2H), 4.52(d,1H), 7.00(d, 1H), 7.21(d, 1H), 7.40(d, 2H), 7.59(m, 2H). LRMS: m/z(TSP⁺) 502.1, 504.1 [MH⁺]Microanalysis found: C, 63.30; H, 6.68; N,8.16. # C₂₇H₃₃Cl₂N₃O₂; 0.15CH₂Cl₂ requires C, 63.29; H, 6.51; N, 8.16%.27^(1b)

50 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.62-1.88(m, 6H), 2.07-2.39(m,5H), 2.58(m, 4H), 2.90(m, 4H), 3.58(m, 4H), 3.90(d, 1H), 4.58(d, 1H),7.01(d, 1H), 7.24(d, 1H), 7.42(d, 2H), 7.60(m, 2H). LRMS: m/z (ES⁺) 488,490 [MH⁺]Microanalysis found: C, 62.96; H, 6.50; N, 8.45. C₂₆H₃₁N₃O₂Cl₂;0.1CH₂Cl₂ requires C, 63.08; H, 6.33; N, 8.46% 28^(c)

51 clear oil ¹Hnmr (CDCl₃, 400MHz) δ: 1.68(m, 2H), 1.82-2.04(m, 8H),2.14(m, 2H), 2.26(m, 2H), 2.50(s, 3H), 2.58(m, 1H), 2.84(m, 2H), 3.90(d,1H), 4.62(d, 1H), 6.96(d, 1H), 7.08(m, 2H), 7.22(m, 1H), 7.38(m, 2H),7.58(m, 3H), 8.46(d, 1H). LRMS: m/z (TSP⁺) 523.9, 525.9 [MH⁺] 29^(d)

42 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.65(m, 4H), 1.82-2.08(m, 5H),2.18(m, 2H), 2.30(m, 2H), 2.40(m, 1H), 2.60(m, 1H), 2.90(m, 2H), 4.00(d,1H), 4.66(d, 1H), 7.18(m, 4H), 7.28(m, 3H), 7.41(d, 1H), 7.52(s, 1H),7.72(m, 2H), 8.50(d, 1H). LRMS: m/z (ES⁺) 552, 554 [MH⁺] 30^(e)

18 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.86-2.19(m, 8H), 2.34(m, 6H),2.48(m, 5H), 3.86(m, 1H), 4.62(m, 1H), 5.15(bs, 2H), 6.98(m, 1H),7.22(m, 2H), 7.34(m, 4H), 7.39(m, 2H), 7.57(m, 2H). LRMS: m/z (TSP⁺)566.1, 568.1 [MH⁺] 31^(f)

33 ¹Hnmr (CDCl₃, 400MHz) δ: 1.96(m, 2H), 2.05(m, 1H), 2.16(m, 2H),2.40(m, 3H), 2.50(m, 5H), 3.45(m, 2H), 3.90(d, 1H), 4.68(d, 1H), 6.58(d,2H), 6.96(d, 1H), 7.22(s, 1H), 7.40(m, 3H), 7.58(d, 2H), 8.15(d, 1H).LRMS: m/z (TSP⁺) 524.9, 526.9 [MH⁺]

EXAMPLE 32(5S)-5-(3.4-Dichlorophenyl)-1-(2-pyridinyl)-5-(2-{[2-(4-pyridinyloxy)ethyl]amino}ethyl)-2-piperidinoneTrihydrochloride

[0197]

[0198] A solution of 2-(4-pyridinyloxy)ethylamine (EP 982322) (90.6 mg,0.66 mmol) in dichloromethane (0.5 ml) was added to a solution of thealdehyde from preparation 11a (238.2 mg, 0.66 mmol) in dichloromethane(10 ml), and the solution stirred for 5 minutes. Sodiumtriacetoxyborohydride (139 mg, 0.66 mmol) was added and the reactionstirred for 1 hour. The reaction was washed with aqueous sodiumbicarbonate solution (20 ml), brine (20 ml), then dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(90:10:1) as eluant. The product was dissolved in a minimum volume ofdichloromethane, 1N ethereal hydrochloric acid added, and the mixtureevaporated under reduced pressure to afford the title compound as awhite foam, 170 mg.

[0199]¹Hnmr (CD₃OD, 400 MHz) δ: 2.24-2.47 (m, 3H), 2.47-2.60 (m, 2H),2.77-2.92 (m, 2H), 3.01 (m, 1H), 3.73 (s, 2H), 4.29 (d, 1H), 4.45 (d,1H), 4.64 (s, 2H), 7.45 (d, 1H), 7.60 (m, 3H), 7.73 (s, 1H), 7.80 (dd,1H), 8.07 (d, 1H), 8.61 (d, 2H), 8.72 (d, 2H).

[0200] LRMS: m/z (TSP⁺) 485.1, 487.2 [MH⁺]

[0201] Microanalysis found: C, 45.06; H, 5.32; N, 8.19.C₂₅H₂₆Cl₂N₃O₂;3HCl;4H₂O requires C, 45.03; H, 5.59; N, 8.40%.

EXAMPLES 33 TO 40

[0202] The following examples of general structure:

[0203] were prepared from the aldehyde from preparation 11a, and theapropriate amines, following a similar procedure to that described inexample 32. Yield Example R (%) Data 33^(1a)

53 white solid ¹Hnmr (CD₃OD, 400MHz) δ: 2.19-2.49(m, 3H), 2.49-2.65(m,2H), 2.88-2.97(m, 2H), 2.97-3.17(m, 1H), 3.52(s, 2H), 4.28(d, 1H),4.46(d, 1H), 4.57(m, 2H), 7.47(d, 1H), 7.60(d, 1H), 7.73(s, 1H), 7.80(d,1H), 8.00-8.17(m, 2H), 8.32(d, 1H), 8.59-8.67(m, 3H), 8.70(s, 1H).Microanalysis found: C, 46.30; H, 5.29; N, 8.39. C₂₅H₂₆Cl₂N₃O₂; 3HCl;3H₂O requires # C, 46.28; H, 5.44; N, 8.64%. 34^(1b)

48 white solid ¹Hnmr (CD₃OD, 400MHz) δ: 2.23-2.45(m, 3H), 2.45-2.62(m,2H), 2.79-2.95(m, 2H), 3.00(t, 1H), 3.50(m, 2H), 4.28(d, 1H), 4.46(d,1H), 4.69(m, 2H), 7.29-7.41(m, 2H), 7.46(d, 1H), 7.60(d, 1H), 7.73(s,1H), 7.80(dd, 1H), 8.06(d, 1H), 8.23(dd, 1H), 8.35(d, 1H), 8.52-8.69(m,2H). LRMS: m/z (TSP⁺) 485.2, 487.2 [MH⁺]Microanalysis found: C, 45.82;H, 5.33; # N, 8.25. C₂₅H₂₆Cl₂N₃O₂; 3HCl; 3.5H₂O requires C, 45.64; H,5.52; N, 8.52%. 35^(2c)

39 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.80-2.02(m, 2H), 2.12(m, 1H),2.20-2.36(m, 3H), 2.40(m, 1H), 2.57(m, 1H), 3.35-3.55(m, 5H), 3.91(d,1H), 4.59(d, 1H), 6.02(d, 1H), 6.38(s, 1H), 7.06-7.23(m, 3H), 7.38(d,1H), 7.43(s, 1H), 7.61-7.77(m, 2H), 8.47(d, 1H). LRMS: m/z (TSP⁺) 485.3,487.3 [MH⁺] 36^(1d)

62 white foam ¹Hnmr (CD₃OD, 400MHz) δ: 2.17(m, 2H), 2.21-2.40(m, 4H),2.53(m, 2H), 2.78(m, 2H), 2.92(m, 1H), 3.06(t, 1H), 3.17(t, 2H), 3.26(m,4H), 3.83(m, 2H), 4.04(m, 2H), 4.20(m, 1H), 4.48(m, 1H), 7.44(d, 1H),7.60(d, 1H), 7.68(dd, 1H), 7.71(s, 1H), 7.93(d, 1H), 8.40(dd, 1H),8.59(d, 1H). LRMS: m/z (TSP⁺) 491.2, 493.2 [MH⁺] 37^(1e)

52 white solid ¹Hnmr (CD₃OD, 400MHz) δ: 1.60(d, 3H), 2.04-2.33(m, 3H),2.37-2.43(m, 3H), 2.61-2.83(m, 2H), 4.15(d, 1H), 4.28(q, 1H), 4.40(d,1H), 7.24-7.40(m, 6H), 7.46(d, 1H), 7.58(s, 1H), 7.61(dd, 1H), 7.82(d,1H), 8.32(dd, 1H), 8.57(d, 1H). LRMS: m/z (TSP⁺) 468.1, 470.1 [MH⁺]38^(1f)

71 white solid ¹Hnmr (CD₃OD, 400MHz) δ: 1.60(d, 3H), 2.05-2.20(m, 1H),2.20-2.40(m, 2H), 2.40-2.57(m, 2H), 2.57-2.66(m, 2H), 2.70-2.81(m, 1H),4.18(d, 1H), 4.35(m, 2H), 7.23-7.42(m, 6H), 7.46(d, 1H), 7.60(s, 1H),7.75(dd, 1H), 7.65(d, 1H), 8.50(dd, 1H), 8.57(d, 1H). LRMS: m/z (TSP⁺)468.1, 470.1 [MH⁺]Microanalysis found: C, 53.31; H, 5.69; N, 6.82. #C₂₆H₂₇Cl₂N₃O; 2HCl; 2.3H₂O requires C, 53.58; H, 5.81; N, 7.21%. 39^(g)

¹Hnmr (CD₃OD, 400MHz) δ: 2.00-2.27(m, 6H), 2.37(m, 1H), 2.35(m, 1H),2.52(m, 2H), 2.70-3.24(m, 6H), 3.55(m, 1H), 3.68(m, 1H), 3.81(m, 2H),4.03(m, 1H), 4.21(m, 2H), 4.42(m, 1H), 7.43(m, 1H), 7.60(m, 1H), 7.70(m,1H), 7.81(m, 1H), 8.07(m, 1H), 8.60(m, 1H). LRMS: m/z (TSP⁺) 489.1,491.2 [MH⁺] 40^(h)

46 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.25(m, 3H), 2.04-2.72(m, 14H),2.80(m, 2H), 3.35(m, 1H), 4.20(m, 3H), 4.80(m, 1H), 7.20(m, 1H), 7.39(m,1H), 7.50(m, 2H), 7.80(m, 2H), 8.50(m, 1H). LRMS: m/z (TSP⁺) 504.1,506.1 [MH⁺]

EXAMPLES 41 TO 47

[0204] The following examples of general structure:

[0205] were prepared from the aldehyde from preparation 12a, and theappropriate amines, following a similar procedure to that described inexample 32. Yield Example R (%) Data 41^(a)

53 white powder ¹Hnmr (CD₃OD, 400MHz) δ: 1.58(d, 3H), 2.07-2.28(m, 3H),2.35-2.50(m, 3H), 2.60-2.75(m, 5H), 4.17(d, 1H), 4.20-4.32(m, 2H),7.22-7.39(m, 6H), 7.48(d, 1H), 7.53(s, 1H), 7.67(d, 1H), 7.76(d, 1H),8.44(dd, 1H). LRMS: m/z (TSP⁺) 482.1, 484.1 [MH⁺]Microanalysis found: C,53.87; H, 5.68; N, 6.82. C₂₇H₂₉Cl₂N₃O; 2HCl; 2.35H₂O requires # C,54.25; H, 6.02; N, 7.03%. 42^(b)

24 white foam ¹Hnmr (CD₃OD, 400MHz) δ: 1.58(m, 3H), 2.08(m, 1H),2.18-2.32(m, 2H), 2.37-2.61(m, 4H), 2.61-2.75(m, 4H), 4.13(d, 1H),4.20-4.35(m, 2H), 7.23-7.39(m, 6H), 7.47(d, 1H), 7.57(s, 1H), 7.62(d,1H), 7.69(d, 1H), 8.39(dd, 1H). LRMS: m/z (TSP⁺) 482.1, 484.0[MH⁺]Microanalysis found: C, 53.36; H, 5.95; N, 6.55. C₂₇H₂₉Cl₂N₃O;2HCl; # 3.0H₂O requires C, 53.24; H, 6.12; N, 6.90%. 43^(c)

26 white solid ¹Hnmr (CD₃OD, 400MHz) δ: 2.11(m, 2H), 2.20-2.37(m, 4H),2.41-2.56(m, 2H), 2.68-2.78(m, 4H), 2.86(m, 1H), 3.03(t, 2H), 3.10(t,2H), 3.21(m, 2H), 3.46(m, 2H), 3.79(t, 2H), 4.01(m, 2H), 4.17(d, 1H),4.37(d, 1H), 7.42(d, 1H), 7.55-7.61(m, 2H), 7.72(m, 2H), 8.55(dd, 1H).LRMS: m/z (ES⁺) 505, # 507 [MH⁺] 44^(1d)

47 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.52(m, 2H), 1.88(s, 3H),1.92-2.36(m, 10H), 2.51-2.60(m, 5H), 2.79(m, 1H), 3.86(d, 1H), 4.35(bs,1H), 4.68(d, 1H), 7.00(d, 1H), 7.21(d, 1H), 7.41(m, 2H), 7.56-7.63(m,2H). LRMS: m/z (TSP⁺) 489.1, 491.1 [MH⁺]Microanalysis found: C, 60.17;H, 6.19; N, 11.11. C₂₅H₃₀Cl₂N₄O₂ requires C, 60.24; H, 6.27; N, 11.24%.45^(1e)

55 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.53(m, 2H), 1.91(s, 3H),1.98-2.43(m, 10H), 2.48-2.66(m, 5H), 2.84(m, 1H), 3.92(d, 1H), 4.38(bs,1H), 4.60(d, 1H), 7.02(d, 1H), 7.24(d, 1H), 7.44(m, 2H), 7.57-7.66(m,2H). LRMS: m/z (TSP⁺) 489.2, 491.2 [MH⁺]Microanalysis found: C, 59.52;H, 6.23; N, 10.82. C₂₅H₃₀Cl₂N₄O₂; 0.8H₂O requires C, 59.60; # H, 6.32;N, 11.12%. 46^(1f)

51 white foam ¹Hnmr (CDCl₃, 400MHz) δ (mixture of diastereoisomers):1.55(m, 2H), 1.63-2.33(m, 12H), 2.37-2.59(m, 5H), 2.77, 2.86(d, 3H,60:40), 3.86(2xd, 1H), 4.30, 5.16(m, 1H, 40:60), 4.57(2xd, 1H), 6.96(d,1H), 7.19(d, 1H), 7.37(d, 2H), 7.50-7.60(m, 2H). LRMS: m/z (ES⁺) 503,505 [MH⁺] 47^(1g)

66 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.58(m, 2H), 1.95(d, 2H), 2.08(s,3H), 2.12-2.40(m, 8H), 2.58(s, 3H), 3.40(t, 2H), 3.56(t, 2H), 3.92(d,1H), 4.71(d, 1H), 7.01(d, 1H), 7.23(m, 1H), 7.43(t, 2H), 7.61(m, 2H).LRMS: m/z (TSP⁺) 489.2, 491.2 [MH⁺]Microanalysis found: C, 59.66; H,6.29; N, 10.95. C₂₅H₃₀Cl₂N₄O₂; 0.7H₂O requires C, 59.81; # H, 6.30; N,11.16%.

EXAMPLE 48(5S)-5-(3,4-Dichlorophenyl)-5-[2-[(2-fluorobenzyl)amino]ethyl]-1-(2-pyridinyl)-2-piperidinoneDihydrochloride

[0206]

[0207] 2-Fluorobenzylamine (90 μl, 0.79 mmol) was added to a solution ofthe aldehyde hydrochloride from preparation 11b (250 mg, 0.63 mmol), indichloromethane (5 ml), and the solution stirred for 5 minutes. Sodiumtriacetoxyborohydride (132.6 mg, 0.63 mmol) was added and the reactionstirred for a further 10 minutes. Saturated aqueous sodium bicarbonatesolution (3 ml) was added, the mixture stirred for 10 minutes, thenfiltered through a phase separation filter, and the organic filtrateevaporated. The residue was purified by Biotage® column chromatographyon silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) asthe eluant. The product was redissolved in dichloromethane, 1N etherealhydrochloric acid added, and the solvents evaporated under reducedpressure to afford the title compound as a white solid, 77.4 mg.

[0208]¹Hnmr (CD₃OD, 400 MHz) δ: 2.10-2.36 (m, 3H), 2.36-2.53 (m, 2H),2.60-2.80 (m, 2H), 2.92 (m, 1H), 4.13 (d, 1H), 4.18 (s, 2H), 4.42 (d,1H), 7.12-7.23 (m, 2H), 7.37-7.50 (m, 3H), 7.54 (m, 2H), 7.67 (s, 1H),7.79 (d, 1H), 8.20 (m, 1H), 8.55 (m, 1H).

[0209] LRMS: m/z (TSP⁺) 472.1, 474.1 [MH⁺]

[0210] Microanalysis found: C, 51.92; H, 5.17; N, 7.00.C₂₅H₂₄Cl₂FN₃0.2HCl;1.6H₂O requires C, 52.30; H, 4.78; N, 7.32%.

EXAMPLES 49 TO 53

[0211] The following compounds of general structure:

[0212] were prepared from the aldehyde hydrochloride from preparation11b and the corresponding commercially available amine, following theprocedure described in example 48. Yield Example R (%) Data 49^(a)

25 ¹Hnmr (CD₃OD, 400MHz) δ: 2.12-2.36(m, 3H), 2.38-2.55(m, 2H),2.64-2.80(m, 2H), 2.85(m, 1H), 4.12(d, 1H), 4.19(s, 2H), 4.50(d, 1H),7.16-7.23(m, 3H), 7.40(m, 2H), 7.50(m, 1H), 7.59(d, 1H), 7.70(d, 1H),7.74(d, 1H), 8.16(m, 1H), 8.50(m, 1H). LRMS: m/z (TSP⁺) 472.1, 474.1[MH⁺]Microanalysis found: C, 52.42; H, 5.22; N, 7.03. C₂₅H₂₄Cl₂FN₃O;2HCl; # 1.5H₂O requires C, 52.46; H, 4.76; N, 7.34% 50^(b)

31 ¹Hnmr (CD₃OD, 400MHz) δ: 2.17-2.40(m, 3H), 2.40-2.57(m, 2H),2.65-2.82(m, 2H), 2.91(m, 1H), 4.09(s, 2H), 4.20(d, 1H), 4.41(d, 1H),7.10(m, 2H), 7.32-7.49(m, 3H), 7.57(d, 1H), 7.66(m, 2H), 7.91(d, 1H),8.41(dd, 1H), 8.58(d, 1H). LRMS: m/z (TSP⁺) 472.1, 474.2[MH⁺]Microanalysis found: C, 51.12; H, 5.04; N, 6.76.C₂₅H₂₄Cl₂FN₃O.2HCl; # 2.5H₂O requires C, 50.86; H, 4.95; N, 7.12% 51^(c)

16 ¹Hnmr (CD₃OD, 400MHz) δ: 2.19-2.40(m, 3H), 2.43-2.60(m, 2H),2.68-2.83(m, 2H), 2.83-2.98(m, 1H), 3.85(s, 3H), 4.15(s, 2H), 4.24(d,1H), 4.43(d, 1H), 6.90-7.13(m, 2H), 7.31(d, 1H), 7.39-7.50(m, 2H),7.59(d, 1H), 7.70(s, 1H), 7.77(dd, 1H), 8.00(d, 1H), 8.52(dd, 1H),8.60(d, 1H). LRMS: m/z (TSP⁺) 484.2, 486.2 [MH⁺]Microanalysis found: C,51.60; H, 5.56; # N, 6.72. C₂₆H₂₇Cl₂N₃O₂; 2HCl; 2.5H₂O requires C,51.84; H, 5.69; N, 6.97% 52^(d)

11 ¹Hnmr (CD₃OD, 400MHz) δ: 2.19-2.40(m, 3H), 2.42-2.60(m, 2H),2.71-2.86(m, 2H), 2.92(m, 1H), 3.81(s, 3H), 4.10(s, 2H), 4.22(d, 1H),4.43(d, 1H), 6.90-7.11(m, 3H), 7.33(dd, 1H), 7.42(d, 1H), 7.59(d, 1H),7.69(s, 1H), 7.75(dd, 1H), 7.99(d, 1H), 8.48(dd, 1H), 8.60(d, 1H). LRMS:m/z (TSP⁺) 484.2, 486.1 [MH⁺]Microanalysis found: C, 52.10; H, 5.46; N,# 6.97. C₂₆H₂₇Cl₂N₃O₂; 2HCl; 2.5H₂O requires C, 51.84; H, 5.69; N, 6.97%53^(e)

8 ¹Hnmr (CD₃OD, 400MHz) δ: 2.13-2.40(m, 3H), 2.40-2.58(m, 2H),2.65-2.82(m, 2H), 2.82-2.95(m, 1H), 3.80(s, 3H), 4.05(s, 2H), 4.20(d,1H), 4.44(d, 1H), 6.93(d, 2H), 7.32(d, 2H), 7.42(d, 1H), 7.59(d, 1H),7.63-7.76(m, 2H), 7.92(d, 1H), 8.40(dd, 1H), 8.59(d, 1H). LRMS: m/z(TSP⁺) 484.2, 486.2 [MH⁺]Microanalysis found: C, 51.14; H, 5.70; N,6.65. C₂₆H₂₇Cl₂N₃O₂; # 2HCl; 3H₂O requires C, 51.07; H, 5.77; N, 6.91%

EXAMPLE 54 tert-butyl1-{2-[(3S)-3-(3,4-dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinylcarbamate

[0213]

[0214] Triethylamine (0.15 ml, 1.1 mmol) was added to a solution of thealdehyde hydrochloride from preparation 11b (400 mg, 1.0 mmol) indichloromethane (5 ml), and the solution stirred for 5 minutes.Tert-butyl 4-piperidinylcarbamate (240 mg, 1.2 mmol) and sodiumtriacetoxyborohydride (295 mg, 1.4 mmol) were then added, and thereaction stirred at room temperature for 3 days. Methanol was added, themixture stirred for 15 minutes, then evaporated under reduced pressure.The residue was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (90:10:1) as eluant to give thetitle compound as a white foam, 580 mg.

[0215]¹Hnmr (CDCl₃, 400 MHz) δ: 1.28 (m, 2H), 1.39 (s, 9H), 1.78-2.00(m, 7H), 2.11 (m, 2H), 2.27 (m, 2H), 2.56 (m, 1H), 2.62 (m, 2H), 3.36(m, 1H), 3.88 (d, 1H), 4.31 (bs, 1H), 4.58 (d, 1H), 7.10 (dd, 1H), 7.17(d, 1H), 7.36 (d, 1H), 7.43 (d, 1H), 7.67 (s, 2H), 8.45 (d, 1H).

[0216] LRMS: m/z (ES⁺) 547, 549 [MH⁺]

[0217] Microanalysis found: C, 71.17; H, 6.63; N, 10.23. C₂₈H₃₆Cl₂N₄O₃requires C, 61.42; H, 6.63; N, 10.23%.

EXAMPLE 55(5S)-5-(3,4-Dichlorophenyl)-1-(2-pyridinyl)-5-{2-[(4-pyridinylmethyl)amino]ethyl-2-piperidinoneHydrochloride

[0218]

[0219] The aldehyde from preparation 11a (192 mg, 0.53 mmol) and4-(aminomethyl)-pyridine (54 μl, 0.53 mmol) in dichloromethane (10 ml)were stirred together for 5 minutes, then acetic acid (61 μl, 1.06 mmol)and sodium triacetoxyborohydride (224 mg, 1.06 mmol) were added, and thereaction stirred at room temperature for 18 hours. The mixture waswashed with aqueous 1N sodium hydroxide solution (5 ml), dried (MgSO₄)and concentrated under reduced pressure. The residual oil was purifiedby column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to give asticky foam. This product was dissolved in dichloromethane (2 ml),treated with ethereal hydrochloric acid and the mixture evaporated underreduced pressure to give the title compound as a white powder, 208 mg.

[0220]¹Hnmr (CD₃OD, 400 MHz) δ: 2.30-2.55 (m, 5H), 2.80 (m, 1H), 2.92(m, 1H), 3.09 (m, 1H), 4.21 (d, 1H), 4.50 (d, 1H), 4.52 (s, 2H), 7.49(dd, 1H), 7.61 (d, 1H), 7.67 (dd, 1H), 7.75 (s, 1H), 7.92 (d, 1H), 8.22(d, 2H), 8.38 (dd, 1H), 8.59 (d, 1H), 8.95 (d, 2H).

[0221] LRMS: m/z (TSP⁺) 455.0, 457.1 [MH⁺]

[0222] Microanalysis found: C, 47.68; H, 5.07; N, 9.17.C₂₄H₂₄Cl₂N₄0;3HCl;0.5H₂O;0.5CH₂Cl₂ requires C, 47.68; H, 5.07; N, 9.17%.

EXAMPLES 56 TO 57

[0223] The compounds of the following general structure:

[0224] were prepared form the aldehyde from preparation 11a, and theappropriate amine, following a similar procedure to that described inexample 55. R Yield (%) Data 56^(1a)

59 white solid ¹Hnmr(CD₃OD, 400MHz) δ: 2.21-2.60(m, 5H), 2.75-2.95(m,2H), 3.05(m, 1H), 4.26(d, 1H), 4.40(s, 2H), 4.43(d, 1H), 7.42(d, 1H),7.58(d, 1H), 7.65(d, 1H), 7.71(m, 2H), 7.76(m, 1H), 8.01(d, 1H),8.13(dd, 1H), 8.56(dd, 1H), 8.60(d, 1H), 8.70(d, 1H). LRMS: m/z (TSP⁺)455.0, 457.1 [MH⁺]Microanalysis found: C, 46.29; H, 5.27; N, 8.80.C₂₄H₂₄Cl₂N₄O; 3HCl; # 2H₂O requires C, 46.58; H, 5.05; N, 9.05% 57^(b)

58 yellow solid ¹Hnmr(CD₃OD, 300MHz) δ: 2.20-2.40(m, 5H), 2.79(m, 2H),2.97(m, 1H), 3.59(m, 4H), 4.23(m, 1H), 4.48(m, 1H), 7.48(m, 1H), 7.61(m,1H), 7.70(m, 1H), 7.76(m, 1H), 7.96(m, 1H), 8.10(m, 2H), 8.41(m, 1H),8.60(m, 1H), 8.82(m, 2H). Microanalysis found: C, 46.46; H, 5.71; N,8.78. C₂₅H₂₆Cl₂N₄O; 3HCl; 3H₂O; 0.2CH₂Cl₂ # requires C, 46.58; H, 5.49;N, 8.62%.

EXAMPLE 581-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinecarboxamide

[0225]

[0226] Isonipecotamide (128 mg, 1 mmol) and glacial acetic acid (120 mg,2 mmol) were added to a solution of the aldehyde from preparation 11a(400 mg, 1 mmol) in dichloromethane (10 ml) and the solution stirred atroom temperature for 30 minutes. Sodium triacetoxyborohydride (212 mg, 2mmol) was added and the reaction stirred at room temperature for 4hours. The reaction was quenched with methanol (10 ml), the solutionstirred for 10 minutes, then concentrated under reduced pressure. Thecrude product was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (90:10:1) as eluant to afford thetitle compound as a colourless foam, 162 mg.

[0227]¹Hnmr (CDCl₃, 400 MHz) δ: 1.74-2.17 (m, 11H), 2.26 (m, 2H), 2.55(m, 1H), 2.75 (m, 2H), 3.42 (m, 1H), 3.86 (dd, 1H), 4.61 (dd, 1H), 5.21(bs, 1H), 5.38 (bs, 1H), 7.08 (m, 1H), 7.19 (m, 1H), 7.36 (m, 1H), 7.42(s, 1H), 7.62 (m, 2H), 8.42 (m, 1H).

[0228] LRMS: m/z (ES⁺) 475, 477 (MH⁺)

[0229] Microanalysis found: C, 57.95; H, 6.06; N, 11.02.C₂₄H₂₈Cl₂N₄O₂;H₂O requires C, 58.08; H, 6.06; N, 11.01%.

EXAMPLE 59(5S)-5-{2-[(1-Acetyl-4-piperidinyl)amino]ethyl}-5-(3,4-dichlorophenyl)-1-(2-pyridinyl)-2-piperidinone

[0230]

[0231] The title compound was prepared as a white foam in 71% yield,from the aldehyde from preparation 11a and the amine from preparation22, following a similar procedure to that described in example 58.

[0232]¹Hnmr (CDCl₃, 400 MHz) δ: 1.10 (t, 2H), 1.70 (s, 2H), 1.85 (m,1H), 1.92 (m, 1H), 2.00 (s, 3H), 2.10 (m, 1H), 2.25 (m, 3H), 2.40-2.70(m, 4H), 2.95 (t, 1H), 3.65 (d, 1H), 3.90 (d, 1H), 4.30 (t, 1H), 4.55(dd, 1H), 7.10 (dd, 1H), 7.19 (d, 1H), 7.38 (d, 1H), 7.45 (d, 1H), 7.68(d, 2H), 8.45 (d, 1H).

[0233] LRMS: m/z (TSP⁺) 489.1, 491.1 [MH⁺]

[0234] Microanalysis found: C, 58.91; H, 6.27; N, 10.85.C₂₅H₃₀Cl₂N₄O₂;0.3CH₂Cl₂ requires C, 59.07; H, 5.99; N, 10.88%.

EXAMPLE 60(5S)-5-(3,4-Dichlorophenyl)-5-(2-{[2-(4-morpholinyl)ethyl]amino}ethyl)-1-(2-pyridinyl)-2-piperidinoneTrihydrochloride

[0235]

[0236] 2-(4-Morpholinyl)ethylamine (970 mg, 7.5 mmol), acetic acid (10drops), and sodium triacetoxyborohydride (500 mg, 2.4 mmol) were addedconsecutively to a solution of the aldehyde from preparation 11a (270mg, 0.68 mmol), and the reaction stirred at room temperature for anhour. The mixture was washed with 1N sodium hydroxide solution, thenbrine, dried (MgSO₄) and concentrated under reduced pressure. Theproduct was redissolved in dichloromethane, treated with 1N etherealhydrochloric acid and the solution evaporated under reduced pressure toafford the title compound as a yellow solid, 220 mg.

[0237]¹Hnmr (CD₃OD, 300 MHz) δ: 2.35 (m, 3H), 2.54 (m, 2H), 2.83 (m,2H), 2.98 (m, 1H), 3.23 (m, 2H), 3.42-3.66 (m, 6H), 3.87-4.12 (m, 4H),4.23 (m, 1H), 4.48 (m, 1H), 7.48 (m, 1H), 7.61 (m, 1H), 7.75 (m, 2H),7.98 (m, 1H), 8.47 (m, 1H), 8.61 (m, 1H).

[0238] LRMS: m/z (ES⁺) 477, 479 [MH⁺]

[0239] Microanalysis found: C, 44.94; H, 6.17; N, 8.72.

[0240] C₂₄H₃₀Cl₂N₄O₂;3HCl;2H₂O;0.25CH₂Cl₂ requires C, 45.22; H, 5.87; N,8.70%.

EXAMPLE 61(5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-methoxy-1-piperidinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0241]

[0242] 4-Methoxypiperidine (WO 9847876) (81 mg, 0.7 mmol) was added to asolution of the aldehyde hydrochloride from preparation 11b (200 mg, 0.5mmol) in dichloromethane (4 ml) and triethylamine (100 μl, 0.7 mmol),and the solution stirred at room temperature for 10 minutes. Sodiumtriacetoxyborohydride (158 mg, 1.5 mmol) and acetic acid (6 μl, 2 mmol)were added and the reaction stirred at room temperature for 2 hours. Thereaction was quenched with methanol, and the solution concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (95:5:0 to 90:10:1) to give thetitle compound as a white foam, 182 mg.

[0243]¹Hnmr (CDCl₃, 400 MHz) δ: 1.57 (s, 2H), 1.85-2.11 (m, 7H), 2.24(m, 4H), 2.55 (m, 3H), 3.19 (s, 1H), 3.24 (s, 3H), 3.85 (d, 1H), 4.58(d, 1H), 7.06 (m, 1H), 7.18 (d, 1H), 7.36 (d, 1H), 7.41 (s, 1H), 7.62(s, 2H), 7.42 (d, 1H).

[0244] LRMS: m/z (ES⁺) 462, 464 [MH⁺]

EXAMPLES 62 TO 72

[0245] The following examples of general structure:

[0246] were prepared from the aldehyde hydrochloride from preparation11b and the appropriate amines, following a similar procedure to thatdescribed in example 61. Yield R (%) Data 62^(a)

39 foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.53(m, 2H), 1.81(m, 2H), 1.95(m, 5H),2.11(m, 2H), 2.27(m, 2H), 2.57(m, 3H), 3.25(m, 1H), 3.32(s, 3H), 3.47(d,2H), 3.51(d, 2H), 3.87(d, 1H), 4.58(d, 1H), 7.09(dd, 1H), 7.18(d, 1H),7.35(d, 1H), 7.43(s, 1H), 7.65(s, 2H), 8.44(dd, 1H). LRMS: m/z (ES⁺)506, 508 [MH⁺] 63^(b)

78 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.66(m, 2H), 1.80(m, 2H),1.88-1.98(m, 3H), 2.07(m, 4H), 2.27(m, 2H), 2.51(m, 3H), 2.72(s, 3H),3.88(d, 1H), 4.51(s, 1H), 4.61(d, 2H), 7.09(dd, 1H), 7.18(d, 1H),7.36(d, 1H), 7.44(s, 1H), 7.66(s, 2H), 8.44(dd, 1H). Microanalysisfound: C, 58.27; H, 6.02; N, 10.61. C₂₅H₃₀Cl₂N₄O₃; 0.15CH₂Cl₂ requiresC, 58.30; H, 5.89; N, 10.81% 64^(c)

49 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.30(m, 2H), 1.80-2.00(m, 10H),2.14(m, 2H), 2.30(m, 2H), 2.58(m, 1H), 2.69(m, 2H), 3.73(m, 1H), 3.92(d,1H), 4.59(d, 1H), 5.26(d, 1H), 7.15(dd, 1H), 7.20(d, 1H), 7.40(d, 1H),7.47(s, 1H), 7.70(s, 2H), 8.48(d, 1H). LRMS: m/z (TSP⁺) 489.1, 491.2[MH⁺] 65^(d)

48 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.20(t, 3H), 1.52(s, 4H), 1.88(m,4H), 1.98(m, 1H), 2.10(m, 2H), 2.26(m, 2H), 2.54(m, 1H), 2.69(s, 3H),2.76(m, 2H), 3.76(bs, 1H), 3.90(d, 1H), 4.08(q, 2H), 4.60(d, 1H),7.09(dd, 1H), 7.18(d, 1H), 7.36(d, 1H), 7.44(s, 1H), 7.67(s, 2H),8.45(dd, 1H). Microanalysis found: C, 60.08; H, 6.48; N, 10.21.C₂₇H₃₄Cl₂N₄O₃; 0.1CH₂Cl₂ requires # C, 60.06; H, 6.36; N. 10.34%. 66^(e)

48 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.46(m, 2H), 1.64(m, 2H), 1.77(m,7H), 1.97(m, 4H), 2.13(m, 2H), 2.30(m, 2H), 2.54(m, 4H), 2.76(dd, 2H),3.92(d, 1H), 4.56(d, 1H), 7.13(dd, 1H), 7.26(d, 1H), 7.39(d, 1H),7.48(s, 1H), 7.68(m, 2H), 8.48(d, 1H). LRMS: m/z (ES⁺) 501, 503 [MH⁺]67^(f)

42 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.57(m, 3H), 1.90-1.98(m, 8H),2.13(m, 2H), 2.31(m, 2H), 2.37(m, 2H), 2.58(m, 1H), 2.79(m, 2H), 3.30(t,2H), 3.90(m, 1H), 3.93(d, 1H), 4.60(d, 1H), 7.13(m, 1H), 7.23(d, 1H),7.40(d, 1H), 7.47(s, 1H), 7.70(s, 2H), 8.48(d, 1H). LRMS: m/z (ES⁺) 515,517 [MH⁺] 68^(g)

51 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.50(m, 2H), 1.80-2.00(m, 5H),2.10(m, 2H), 2.20-2.40(m, 4H), 2.56(m, 1H), 2.80(m, 2H), 3.80(m, 1H),3.86(s, 2H), 3.90(d, 1H), 4.60(d, 1H), 5.15(s, 1H), 7.10(m, 1H), 7.20(d,1H), 7.36(d, 1H), 7.45(s, 1H), 7.67(d, 2H), 8.46(d, 1H). LRMS: m/z (ES⁺)530, 532 [MH⁺] 69^(h)

63 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.63(t, 4H), 1.88(m, 2H), 2.00(m,1H), 2.11(m, 2H), 2.22-2.40(m, 6H), 2.53(m, 1H), 3.88(m, 5H), 4.62(d,1H), 7.09(dd, 1H), 7.18(d, 1H), 7.37(d, 1H), 7.43(s, 1H), 7.65(s, 2H),8.43(d, 1H). LRMS: m/z (TSP⁺) 490.2, 492.2 [MH⁺] 70^(i)

30 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.61(m, 2H), 1.66(m, 2H), 1.96(m,5H), 2.12(m, 2H), 2.27(m, 2H), 2.57(m, 1H), 2.88(m, 3H), 3.75(s, 3H),3.94(d, 1H), 4.64(d, 1H), 6.80(d, 1H), 6.91(m, 1H), 7.10(m, 3H), 7.23(m,1H), 7.38(d, 1H), 7.47(s, 1H), 7.68(d, 2H), 8.47(m, 1H). LRMS: m/z (ES⁺)538, 540 [MH⁺] # Microanalysis found: C, 66.09; H, 6.20; N, 7.67.C₃₀H₃₃Cl₂N₃O₂; 0.1CH₂Cl₂ requires C, 66.09; H, 6.12; N, 7.68%. 71^(j)

84 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.62(m, 4H), 1.97(m, 4H), 2.15(m,2H), 2.29(m, 3H), 2.56(dd, 1H), 2.73(bs, 1H), 3.07(m, 2H), 3.94(d, 1H),4.63(d, 1H), 7.12(m, 3H), 7.23(d, 1H), 7.41(d, 1H), 7.48(s, 1H),7.59(dd, 1H), 7.69(m, 2H), 8.45(m, 2H). LRMS: m/z (ES⁺) 509, 511 [MH⁺]72^(k)

97 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.95(m, 2H), 2.04(m, 1H), 2.15(m,2H), 2.28(m, 2H), 2.38(m, 4H), 2.58(m, 1H), 3.44(m, 4H), 3.92(d, 1H),4.63(d, 1H), 6.58(d, 2H), 7.09(m, 1H), 7.20(d, 1H), 7.38(d, 1H), 7.42(m,1H), 7.46(s, 1H), 7.66(s, 2H), 8.12(d, 1H), 8.43(d, 1H). LRMS: m/z (ES⁺)510, 512 [MH⁺]

EXAMPLE 73(5S)-5-(3,4-Dichlorophenyl)-5-{2-[3-(4-hydroxy-1-piperidinyl)-1-azetidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone

[0247]

[0248] Triethylamine (1 ml, 7.2 mmol) and acetic acid (1.1 ml, 18.3mmol) were added to a solution of 1-(3-azetidinyl)-4-piperidinoltrifluoroacetate (WO 9605193) (250 mg, 0.93 mmol), the aldehyde frompreparation 11a (250 mg, 0.62 mmol) and sodium triacetoxyborohydride(250 mg, 1.2 mmol) in dichloromethane (100 ml) and the reaction stirredat room temperature for 90 minutes. The solution was washed with water,dried (MgSO₄), and concentrated under reduced pressure. The residual gumwas purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol (100:0 to 95:5) to afford the titlecompound as a yellow solid, 82 mg.

[0249]¹Hnmr (CDCl₃, 400 MHz) δ:1.55-2.40 (m, 14H), 2.60 (m, 3H), 2.80(m, 2H), 2.95 (m, 1H), 3.52 (m, 2H), 3.75 (m, 1H), 3.95 (d, 1H), 4.58(d, 1H), 7.20 (m, 2H), 7.40 (dd, 2H), 7.74 (m, 2H), 8.50 (d, 1H).

[0250] LRMS: m/z (TSP⁺) 503.1, 505.1 [MH⁺]

EXAMPLES 74 TO 85

[0251] The following examples of general structure:

[0252] were prepared from the aldehyde from preparation 11a and theappropriate amines, following a similar procdure to that described inexample 73. Yield Example R (%) Data 74^(a)

43 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.25(s, 3H), 1.50-2.00(m, 8H),2.18(m, 4H), 2.34(m, 4H), 2.60(m, 1H), 2.75(m, 2H), 2.95(m, 1H), 3.44(t,2H), 3.90(d, 1H), 4.48(d, 1H), 6.55(d, 1H), 7.20(m, 2H), 7.42(d, 1H),7.45(d, 1H), 7.72(d, 1H), 8.50(d, 1H). LRMS: m/z (TSP⁺) 517.9, 519.9[MH⁺]Microanalysis found: C, 60.41; H, 6.75; N, 10.20. C₂₇H₃₄Cl₂N₄O₂; #0.2CH₂Cl₂; 0.4H₂O requires C, 60.31; H, 6.55; N, 10.34%. 75^(b)

60 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.70(m, 1H), 1.82(m, 1H), 2.14(m,2H), 2.30(m, 7H), 2.58(m, 1H), 2.72(m, 2H), 2.90(m, 1H), 3.40(t, 2H),3.68(m, 4H), 3.90(d, 1H), 4.56(d, 1H), 7.16(dd, 1H), 7.20(dd, 1H),7.40(d, 1H), 7.44(s, 1H), 7.70(m, 2H), 8.50(d, 1H). LRMS: m/z (TSP⁺)489.1, 491.1 [MH⁺] 76^(1c)

78 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.78(m, 1H), 1.86(m, 1H),2.10-2.40(m, 5H), 2.57(m, 1H), 3.25(t, 2H), 3.50(t, 2H), 3.95(d, 1H),4.63(d, 1H), 7.15(m, 1H), 7.25(m, 2H), 7.35(m, 2H), 7.40(m, 1H), 7.45(m,3H), 7.70(d, 2H), 8.48(d, 1H). 77^(1d)

32 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.80(m, 1H), 1.92(m, 1H),2.08-2.45(m, 5H), 2.59(m, 1H), 3.42(m, 2H), 3.56(m, 2H), 3.84(s, 3H),3.90(d, 1H), 4.58(d, 1H), 6.88(d, 1H), 6.95(dd, 1H), 7.14(m, 1H),7.20(d, 2H), 7.24(m, 2H), 7.39(d, 1H), 7.44(s, 1H), 7.70(m, 2H), 8.45(d,1H). LRMS: m/z (TSP⁺) 526.1, 528.1 [MH⁺] 78^(1e)

29 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.70(m, 1H), 1.81(m, 1H), 2.10(m,2H), 2.27(m, 4H), 2.38(m, 4H), 2.58(m, 1H), 2.70(m, 3H), 2.77(s, 3H),2.96(m, 1H), 3.21(m, 2H), 3.38(m, 2H), 3.90(d, 1H), 4.57(d, 1H),7.16(dd, 1H), 7.19(d, 1H), 7.41(d, 1H), 7.42(s, 1H), 7.70(m, 2H),8.49(d, 1H). LRMS: m/z (TSP⁺) 566.3 [MH⁺] 79^(f)

25 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.80(m, 1H), 2.0-2.65(m, 12H),2.80(m, 1H), 3.04(m, 1H), 3.96(d, 1H), 4.36(s, 1H), 4.72(d, 1H),7.16(dd, 1H), 7.24(d, 1H), 7.44(d, 1H), 7.50(s, 1H), 7.75(m, 2H),8.48(d, 1H). LRMS: m/z (TSP⁺) 434.1, 436.1 [MH⁺]Microanalysis found: C,57.10; H, 5.73; N, 8.64. C₂₂H₂₅Cl₂N₃O₂; 0.4CH₂Cl₂; # 0.25H₂O requires C,56.90; H, 5.61; N, 8.89%. 80^(g)

8 ¹Hnmr(CDCl₃, 400MHz) δ: 1.62(d, 2H), 1.93(m, 5H), 2.18(m, 5H), 2.30(m,2H), 2.62(m, 3H), 3.94(d, 1H), 4.74(d, 1H), 7.16(m, 1H), 7.22(d, 1H),7.41(d, 1H), 7.48(s, 1H), 7.72(s, 2H), 8.48(d, 1H). LRMS: m/z (ES⁺) 516,518 [MH⁺]Microanalysis found: C, 55.52; H, 5.13; N, 7.88.C₂₄H₂₆Cl₂F₃N₃O₂requires C, 55.45; H, 5.11; N, 7.92%. 81^(h)

18 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.50-2.70(m, 24H), 2.88(m, 4H),3.75(m, 1H), 3.91(d, 1H), 4.64(d, 1H), 7.16(m, 1H), 7.24(dd, 1H),7.42(d, 1H), 7.50(s, 1H), 7.72 (s, 2H), 8.50 (d, 1H). LRMS: m/z (TSP⁺)531.2, 533.2 [MH⁺] 82^(i)

53 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.26(m, 2H), 1.44(m, 2H),1.85-2.08(m, 5H), 2.15(m, 2H), 2.26(m, 2H), 2.58(m, 1H), 2.85(m, 2H),3.41(m, 1H), 3.95(d, 1H), 4.61(d, 1H), 7.08(m, 2H), 7.18(m, 3H), 7.38(d,1H), 7.46(s, 1H), 7.64(m, 2H), 8.19(d, 1H), 8.42(d, 1H). LRMS: m/z(TSP⁺) 525.1, 527.2 [MH⁺] 83^(1j)

16 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.58(m, 2H), 1.75(m, 2H),1.81-2.08(m, 5H), 2.15(m, 2H), 2.24-2.40(m, 3H), 2.58(m, 1H), 2.84(m,2H), 3.90(d, 1H), 4.60(d, 1H), 7.02-7.20(m, 4H), 7.38(d, 1H), 7.45(m,1H), 7.68(m, 2H), 8.02(m, 2H), 8.45(m, 1H). 84^(1k)

33 white crystal ¹Hnmr(CDCl₃, 400MHz) δ: 1.58(m, 2H), 1.72(m, 2H),1.83-2.08(m, 5H), 2.16(m, 2H), 2.28(m, 2H), 2.40(m, 1H), 2.55(m, 1H),2.85(m, 2H), 3.90(d, 1H), 4.60(d, 1H), 7.02(d, 2H), 7.10(m, 1H), 7.20(m,1H), 7.38(d, 1H), 7.42(m, 1H), 7.66(m, 2H), 8.08(d, 2H), 8.42(m, 1H).LRMS: m/z (TSP⁺) 525.3, 527.3 [MH⁺] 85^(1l)

37 white foam ¹Hnmr(CDCl₃, 300MHz) δ: 1.94(m, 2H), 2.04(m, 1H), 2.14(m,2H), 2.30(m, 2H), 2.42(m, 4H), 2.58(m, 1H), 3.17(m, 4H), 2.90(d, 1H),4.69(d, 1H), 5.62(s, 1H), 7.12(m, 1H), 7.10(m, 1H), 7.20(m, 1H), 7.39(d,1H), 7.45(s, 1H), 7.68(m, 2H), 8.24(d, 1H), 8.34(m, 2H), 8.45(d, 1H).LRMS: m/z (TSP⁺) 553.2, 555.2 [MH⁺]Microanalysis found: C, 59.34; H,5.58; N, # 14.52. C₂₈H₃₀Cl₂N₆O₂; 0.73H₂O requires C, 59.35; H, 5.60; N,14.83%. 86^(m)

30 white solid ¹Hnmr(CDCl₃, 400MHz) δ: 1.73-1.98(m, 6H), 2.04(2xs, 3H),2.17(m, 2H), 2.28(m, 2H), 2.38-2.62(m, 4H), 3.38-3.58(m, 4H), 3.92(d,1H), 4.66(m, 1H), 7.17(m, 1H), 7.22(m, 1H), 7.41(m, 1H), 7.46(s, 1H),7.72(m, 2H), 8.46(d, 1H). LRMS: m/z (TSP⁺) 489.1, 491.1 [MH⁺]

EXAMPLE 87(5S)-5-(3,4-Dichlorophenyl)-5-{2-[4-hydroxy-4-(trifluoromethyl)-1-piperidinyl]ethyl}-1-(6-methyl-2-pyridinyl)-2-piperidinone

[0253]

[0254] The title compound was obtained as a solid, from the aldehydefrom preparation 12a, and the amine from preparation 58, following asimilar procedure to that described in example 73.

[0255]¹Hnmr (CDCl₃, 400 MHz) δ: 1.62 (m, 4H), 1.82 (m, 2H), 1.94 (t,2H), 2.02-2.18 (m, 5H), 2.30 (m, 2H), 2.50 (s, 3H), 2.58 (d, 1H), 2.68(d, 1H), 3.90 (d, 1H), 4.42 (d, 1H), 6.98 (d, 1H), 7.22 (d, 1H), 7.41(d, 2H), 7.58 (d, 2H).

[0256] LRMS: m/z (TSP⁺) 530.1, 532.1 [MH⁺]

[0257] Microanalysis found: C, 55.39; H, 5.48; N, 7.58.C₂₅H₂₈Cl₂F₃N₃O₂;0.2CH₂Cl₂ requires C, 55.29; H, 5.23; N, 7.68%.

EXAMPLE 88N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidiny]ethyl}-4-phenyl-4-piperidinyl)-N-methylacetamide

[0258]

[0259] Triethylamine (2 ml) and glacial acetic acid (2 ml) were added toa solution of N-methyl-N-(4-phenyl-4-piperidinyl)acetamide (WO 9805640)(97.9 mg, 036 mmol) and the aldehyde hydrochloride from preparation 11b(145 mg, 0.36 mmol) in dichloromethane (20 ml). Sodiumtriacetoxyborohydride (79 mg, 0.37 mmol) was added and the reactionstirred at room temperature for 18 hours. The reaction was neutralisedusing saturated sodium bicarbonate solution, the phases separated andthe organic layer washed with brine, dried (MgSO₄), and concentratedunder reduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(95:5:0.5) as eluant, and azeotroped with diethyl ether to afford thetitle compound as a white foam, 92 mg.

[0260]¹Hnmr (CDCl₃, 400 MHz) δ: 1.86-2.21 (m, 15H), 2.21-2.37 (m, 2H),2.60 (m, 3H), 2.81 (s, 2H), 3.93 (d, 1H), 4.68 (d, 1H), 7.13 (m, 1H),7.20-7.38 (m, 6H), 7.40 (d, 1H), 7.49 (s, 1H), 7.71 (d, 2H), 8.48 (d,1H).

[0261] LRMS: m/z (TSP⁺) 579.1, 581.1 [MH⁺]

[0262] Microanalysis found: C, 63.57; H, 6.72; N, 9.10.C₃₂H₃₆Cl₂N₄O₂;1.3H₂O requires C, 63.74; H, 6.45; N, 9.29%.

EXAMPLES 89 TO 94

[0263] The following examples of general structure:

[0264] were prepared from the aldehyde hydrochloride from preparation11b and the appropriate amine, following a similar procedure to thatdescribed in example 88. Yield Example R (%) Data 89^(a)

62 white foam ¹Hnmr(CDCl₃, 300MHz) δ: 1.43(m, 2H), 1.77(m, 4H), 1.97(m,3H), 2.12(m, 3H), 2.34(m, 2H), 2.52(m, 4H), 2.60(m, 1H), 2.81(m, 2H),3.71(m, 4H), 3.95(d, 1H), 4.63(d, 1H), 7.14(m, 1H), 7.21(d, 1H), 7.41(d,1H), 7.50(s, 1H), 7.72(m, 2H), 8.51(d, 1H). Microanalysis found: C,61.67; H, 6.70; N, 10.63. C₂₇H₃₄Cl₂N₄O₂; 0.5H₂O requires C, 61.59; H,6.70; N, 10.64%. 90^(1b)

19 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.83-2.18(m, 12H), 2.21-2.36(m,4H), 2.49-2.67(m, 3H), 3.91(d, 1H), 4.68(d, 1H), 5.40(bs, 1H), 7.10(m,1H), 7.15-7.32(m, 6H), 7.39(d, 1H), 7.45(s, 1H), 7.66(m, 2H), 8.42(d,1H). LRMS: m/z (TSP⁺) 565.2, 567.2 [MH⁺]Microanalysis found: C, 63.41;H, 6.25; N, 9.54. C₃₁H₃₄Cl₂N₄O₂; 1.2H₂O requires C, 63.24; H, 6.01; N,9.27%. 91^(2c)

62 white foam ¹Hnmr(CDCl₃, 400MHz) δ: 1.59(m, 2H), 1.80-2.70(m, 14H),3.92(d, 1H), 4.72(d, 1H), 5.20(bs, 2H), 7.15(m, 1H), 7.24(m, 3H),7.33-7.46(m, 4H), 7.49(s, 1H), 7.70(m, 2H), 8.44(d, 1H). LRMS: m/z(TSP⁺) 551.1, 553.1 [MH⁺]Microanalysis found: C, 63.28; H, 6.04; N,9.41. C₃₀H₃₂Cl₂N₄O₂; 1.1H₂O requires C, 63.07; H, 6.03; N, 9.81%.92^(2d)

58 off- white foam ¹Hnmr(CDCl₃, 300MHz) δ: 1.62(m, 2H), 1.90-2.50(m,12H), 2.55-2.82(m, 3H), 4.40(d, 1H), 4.69(d, 1H), 7.05-7.29(m, 3H),7.37(d, 1H), 7.42(d, 1H), 7.53(s, 1H), 7.71(m, 3H), 8.50(m, 2H). LRMS:m/z (TSP⁺) 525.1, 527.1 [MH⁺]Microanalysis found: C, 62.77; H, 5.97; N,10.19. C₂₈H₃₀Cl₂N₄O₃; 0.5H₂O requires C, # 62.92; H, 5.85; N, 10.18%.93^(e)

14 ¹Hnmr(CDCl₃, 300MHz) δ: 1.28(t, 3H), 1.84-2.46(m, 12H), 2.46-2.73(m,4H), 3.19(s, 2H), 3.96(d, 1H), 4.19(q, 2H), 4.66(d, 1H), 7.16(m, 1H),7.24(d, 1H), 7.42(d, 1H), 7.49(s, 1H), 7.71(m, 2H), 8.50(d, 1H). LRMS:m/z (TSP⁺) 519.2, 521.3 [MH⁺] 94^(f)

36 white foam ¹Hnmr(CDCl₃, 300MHz) δ: 1.82-2.70(m, 18H), 3.59(t, 2H),3.98(d, 1H), 4.66(d, 1H), 7.16(m, 1H), 7.22(d, 1H), 7.41(d, 1H), 7.51(s,1H), 7.72(m, 2H), 8.50(d, 1H). Microanalysis found: C, 58.37; H, 6.40;N, 10.95. C₂₄H₃₀Cl₂N₄O₂; 0.9H₂O requires C, 58.39; H, 6.40; N, 11.35%.

EXAMPLES 95 TO 96

[0265] The following examples of general structure:

[0266] were prepared from the aldehyde hydrochloride from preparation12b and the appropriate amine, following a similar procedure to thatdescribed in example 88, isolating the compounds after azeotroping withdiethyl ether. Yield Example R (%) Data 95^(a)

37 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.98(m, 2H), 2.07-2.41(m, 5H),2.41-2.66(m, 8H), 2.86(s, 3H), 3.10(t, 4H), 3.92(d, 1H), 4.32(d, 2H),4.77(d, 1H), 5.69(m, 1H), 6.98-7.06(m, 2H), 7.29(d, 1H), 7.44(m, 2H),7.57-7.66(m, 3H), 8.31(d, 1H). LRMS: m/z (TSP⁺) 631.3, 633.3[MH⁺]Microanalysis found: C, 56.45; H, 6.05; N, 12.41. # C₃₀H₃₆Cl₂N₆O₃S;0.5(CH₃CH₂)₂O; 0.5 H₂O requires C, 56.71; H, 6.25; N, 12.40%. 96^(b)

36 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.98(m, 2H), 2.14-2.30(m, 10H),2.30-2.41(m, 2H), 2.41-2.65(m, 7H), 3.26(m, 4H), 3.35(s, 2H), 3.92(d,1H), 4.77(d, 1H), 6.91(dd, 1H), 7.01(d, 1H), 7.31(d, 1H), 7.42(d, 2H),7.56-7.72(m, 3H), 8.20(d, 1H). LRMS: m/z (TSP⁺) 581.1, 583.2[MH⁺]Microanalysis found: C, 63.22; H, 6.61; N, 13.72. C₃₁H₃₈Cl₂N₆O; #0.1(CH₃CH₂)₂O; 0.5H₂O requires C, 63.07; H, 6.74; N, 14.05%.

EXAMPLE 97(5S)-5-(3,4-Dichlorophenyl)-1-[6-(dimethylamino)-2-pyridinyl]-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0267]

[0268] The title compound was obtained as a white foam in 74% yield,after trituration from diethyl ether, from the aldehyde from preparation17 and 3-morpholinoazetidine dihydrochloride (WO 9725322), following asimilar procedure to that described in example 88.

[0269]¹Hnmr (CDCl₃, 400 MHz) δ: 1.63 (m, 1H), 1.79 (m, 1H), 1.98-2.35(m, 9H), 2.41-2.55 (m, 1H), 2.60-2.73 (m, 2H), 2.83 (t, 1H), 3.06 (s,6H), 3.24 (q, 2H), 3.63 (s, 4H), 3.70 (d, 1H), 4.59 (d, 1H), 6.32 (d,1H), 6.81 (d, 1H), 7.28 (d, 1H), 7.36 (d, 1H), 7.43 (dd, 1H), 7.57 (s,1H).

[0270] LRMS: m/z (TSP⁺) 532.2, 534.3 [MH⁺]

[0271] Microanalysis found: C, 60.06; H, 6.69; N, 12.85.C₂₇H₃₅Cl₂N₅O₂;0.35H₂O requires C, 60.19; H, 6.68; N, 13.00%.

EXAMPLE 98N-[1-(2-{(3S)-3-(3,4-Dichlorophenyl)-1-[6-(dimethylamino)-2-pyridinyl]-6-oxopiperidinyl}ethyl)-4-piperidinyl]-N-methylacetamide

[0272]

[0273] The title compound was obtained as a white foam in 67% yield,from the aldehyde from preparation 17 and the amine from preparation 60,following the procedure described in example 88.

[0274] 1 Hnmr (CDCl₃, 400 MHz) δ: 1.42-1.60 (m, 3H), 1.69 (m, 1H),1.77-2.29 (m, 12H), 2.55 (m, 1H), 2.72-2.82 (m, 5H), 3.10 (s, 6H), 4.39(m, 1H), 4.63 (d, 1H), 6.37 (d, 2H), 6.84 (d, 1H), 7.29-7.42 (m, 2H),7.48 (dd, 1H), 7.61 (s, 1H).

[0275] LRMS: m/z (TSP⁺) 546.3, 548.3 [MH⁺]

[0276] Microanalysis found: C, 60.20; H, 6.93; N, 12.40.C₂₈H₃₇Cl₂N₅O₂;0.5H₂O requires C, 60.54; H, 6.89; N, 12.61%.

EXAMPLE 99 tert-Butyl1-{2-[(3S)-3-(3,4-dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl(methyl)carbamate

[0277]

[0278] Triethylamine (1.5 ml, 10.8 mmol) was added to a suspension ofthe aldehyde hydrochloride from preparation 11b (500 mg, 1.25 mmol) andtert-butyl methyl(4-piperidinyl)carbamate (EP 457686) (402 mg, 1.88mmol) in dichloromethane (250 ml), and the mixture stirred at roomtemperature for 5 minutes. Acetic acid (1.5 ml, 26.2 mmol) and sodiumtriacetoxyborohydride (530 mg, 2.5 mmol) were added and the reactionstirred at room temperature for 2 hours. The mixture was washed with 2Nsodium hydroxide solution (200 ml), and the aqueous wash extracted withdichloromethane (2×200 ml). The combined organic solutions were washedwith brine, dried (MgSO₄) and evaporated under reduced pressure. Thecrude product was purified by Biotage® column chromatography on silicagel using an elution gradient of dichloromethane:methanol (100:0 to95:5) to afford the title compound as a white foam, 360 mg.

[0279]¹Hnmr (CDCl₃, 300 MHz) δ: 1.45 (s, 9H), 1.58 (m, 6H), 1.81-2.21(m, 6H), 2.32 (m, 2H), 2.57-2.64 (m, 1H), 2.70 (s, 3H), 2.80 (m, 2H),3.95 (d, 1H), 4.64 (d, 1H), 7.16 (m, 1H), 7.23 (m, 1H), 7.41 (m, 1H),7.50 (s, 1H), 7.72 (m, 2H), 8.50 (m, 1H).

[0280] LRMS: m/z (TSP⁺) 561.2, 563.2 [MH⁺]

[0281] Microanalysis found: C, 61.50; H, 6.87; N, 9.83. C₂₉H₃₈Cl₂N₄O₃requires C, 62.03; H, 6.77; N, 9.98%.

EXAMPLES 100 TO 111

[0282] The following examples of general structure:

[0283] were prepared from the aldehyde hydrochloride from preparation12b and the appropriate amine, following a similar procedure to thatdescribed in example 99, except the products were purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammoniaas eluant. Yield Example R (%) Data 100^(a)

28 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.75(m, 1H), 1.82(m, 1H),2.06-2.18(m, 2H), 2.20-2.08(m, 2H), 2.14(m, 3H), 2.54(m, 3H), 2.79(m,2H), 2.98(m, 1H), 3.03(m, 5H), 3.16(m, 2H), 3.44(m, 2H), 3.82(d, 1H),4.46(d, 1H), 6.97(d, 1H), 7.19(d, 1H), 7.38(m, 2H), 7.55(m, 2H). LRMS:m/z (TSP⁺) 502.8, 504.8 [MH⁺] 101^(b)

27 white solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.56(m, 3H), 1.70(m, 3H),1.92(m, 4H), 2.03(s, 3H), 2.16(m, 2H), 2.30(m, 2H), 2.55(m, 4H), 2.80(s,3H), 3.00(m, 1H), 3.42(m, 1H), 4.40(m, 1H), 4.58(dd, 1H), 7.00(d, 1H),7.22(d, 1H), 7.40(m, 2H), 7.59(d, 2H). LRMS: m/z (TSP⁺) 517.2, 519.2[MH⁺] 102^(c)

61 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.46(m, 2H), 1.88-2.08(m, 8H),2.15(m, 2H), 2.25(m, 2H), 2.54(s, 3H), 2.84(m, 2H), 3.42(m, 1H), 3.90(d,1H), 4.60(d, 1H), 6.98(d, 1H), 7.06(m, 1H), 7.18(m, 3H), 7.39(d, 2H),7.58(m, 2H), 8.20(d, 1H). LRMS: m/z (TSP⁺) 539.2, 541.1 [MH⁺] 103^(1d)

33 ¹Hnmr (CD₃OD, 400MHz) δ: 2.15(m, 4H), 2.50(m, 3H), 2.77(s, 3H),2.80-3.00(m, 4H), 3.08(m, 2H), 3.17(m, 2H), 3.63(m, 2H), 4.20(d, 1H),4.34(d, 1H), 7.42(d, 1H), 7.59(d, 1H), 7.68(m, 2H), 7.80(m, 1H), 7.92(m,1H), 8.22(m, 1H), 8.42(m, 1H), 8.72(m, 1H), 8.91(s, 1H). 104^(1e)

42 ¹Hnmr (CD₃OD, 400MHz) δ: 2.15(m, 4H), 2.39(m, 2H), 2.50(m, 3H),2.77(s, 3H), 2.80-3.00(m, 2H), 3.06(m, 2H), 3.19(m, 2H), 3.63(m, 2H),4.21(d, 1H), 4.34(d, 1H), 7.42(d, 1H), 7.59(d, 1H), 7.68(m, 2H), 7.80(m,1H), 7.95(m, 2H), 8.44(m, 1H), 8.80(m, 2H). LRMS: m/z (TSP⁺) 539.3 [MH⁺]105^(f)

23 pale yellow solid ¹Hnmr (CDCl₃, 400MHz) δ: 1.60(d, 1H), 1.75-2.10(m,7H), 2.18(m, 2H), 2.32(m, 2H), 2.44(m, 2H), 2.56(s, 3H), 2.60(m, 1H),2.75(m, 2H), 3.94(d, 1H), 4.60(d, 1H), 7.00(d, 1H), 7.20(m, 2H), 7.36(d,1H), 7.40(dd, 2H), 7.60(m, 2H), 7.71(dd, 1H), 8.50(d, 1H). LRMS: m/z(ES⁺) 539, 541 [MH⁺]Microanalysis found: C, 63.12; H, 5.94; N, # 9.94.C₂₉H₃₂Cl₂N₄O₂; 0.2CH₂Cl₂ requires C, 63.02; H, 6.12; N, 9.92%. 106^(g)

38 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.65(m, 3H), 1.91-2.40(m, 11H),2.55(s, 3H), 2.63(m, 2H), 3.96(d, 1H), 4.64(d, 1H), 7.01(d, 1H), 7.28(m,3H), 7.40(m, 4H), 7.60(m, 2H). LRMS: m/z (TSP⁺) 573.0, 575.1 [MH⁺]107^(h)

42 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.80-2.37(m, 14H), 2.57(m, 6H),3.54(m, 2H), 3.92(d, 1H), 4.63(d, 1H), 7.00(m, 1H), 7.19-7.43(m, 8H),7.60(m, 2H). LRMS: m/z (ES⁺) 552, 554 [MH⁺] 108^(i)

10 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.94(m, 2H), 2.04-2.20(m, 4H),2.24(m, 2H), 2.50(m, 7H), 3.30(m, 4H), 3.90(d, 1H), 4.64(d, 1H), 6.78(d,1H), 6.80(dd, 1H), 6.97(d, 1H), 7.17(m, 1H), 7.21(m, 1H), 7.40(m, 2H),7.58(m, 2H), 8.12(d, 1H). Microanalysis found: C, 60.14; H, 5.99; N,12.28. C₂₈H₃₁Cl₂N₅O₂; H₂O requires C, 60.22; H, 5.96; N, 12.54%. 109^(j)

72 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.93-2.63(m, 15H), 3.39(m, 4H),3.86(s, 3H), 3.92(d, 1H), 4.74(d, 1H), 6.83(m, 1H), 7.03(dd, 2H),7.28(m, 1H), .7.43(d, 2H), 7.61(m, 2H), 7.88(d, 1H). LRMS: m/z (ES⁺)554, 556 [MH⁺]Microanalysis found: C, 61.92; H, 5.95; N, 11.86.C₂₉H₃₃Cl₂N₅O₂; 0.5H₂O requires C, 61.81; H, 6.08; N, 12.43%. 110^(k)

76 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.97(m, 2H), 2.07-2.62(m, 13H),3.23(m, 4H), 3.92(d, 1H), 4.78(d, 1H), 5.80(s, 1H), 7.03(m, 1H), 7.09(m,1H), 7.28(m, 1H), 7.44(m, 2H), 7.62(m, 2H), 8.30(m, 1H), 8.40(m, 2H).LRMS: m/z (TSP⁺) 568.0, 570.1 [MH⁺]Microanalysis found: C, 60.02; H,5.85; N, 14.25. C₂₉H₃₂N₆Cl₂O₂; 0.2CH₂Cl₂ requires C, # 60.00; H, 5.59;N, 14.38%. 111^(l)

71 white foam ¹Hnmr (CDCl₃, 300MHz) δ: 1.96(m, 2H), 2.04-2.59(m, 13H),3.68(m, 4H), 3.92(d, 1H), 4.74(d, 1H), 6.75(m, 1H), 7.00(d, 1H), 7.27(m,1H), 7.43(m, 2H), 7.61(m, 2H), 7.75(d, 1H), 8.32(s, 1H). LRMS: m/z(TSP⁺) 550.0, 552.0 [MH⁺]Microanalysis found: C, 62.70; H, 5.55; N,14.79. C₂₉H₃₀N₆Cl₂O; 0.1CH₂Cl₂ requires C, 62.64; H, 5.46; N, 15.06%.

EXAMPLE 112(5S)-5-(3,4-Dichlorophenyl)-5-(2-{[(1-oxido-2-pyridinyl)methyl]amino}ethyl)-1-(2-pyridinyl)-2-piperidinone

[0284]

[0285] Triethylamine (287 μl, 2.06 mmol) was added to a suspension ofthe aldehyde from preparation 11a (250 mg, 0.68 mmol) in dichloromethane(10 ml) followed by (1-oxido-2-pyridinyl)methylamine (J.O.C. 1974;39(9); 1250) (136 mg, 0.68 mmol) and the mixture stirred at roomtemperature for 15 minutes. Acetic acid (158 μl, 2.75 mmol) and sodiumtriacetoxyborohydride (292 mg, 1.38 mmol) were added and the reactionstirred at room temperature for 18 hours. The mixture was washed with 2Nsodium hydroxide solution (5 ml), dried (MgSO₄) and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol:0.88 ammonia (95:5:0.5 to 93:7:1) to afford thetitle compound as a white foam, 224 mg.

[0286]¹Hnmr (CDCl₃, 400 MHz) δ: 1.90 (m, 1H), 2.00 (m, 1H), 2.15 (m,1H), 2.28 (m, 3H), 2.47 (m, 1H), 2.58 (m, 1H), 3.85 (s, 2H), 3.90 (d,1H), 4.58 (d, 1H), 7.15 (dd, 1H), 7.19 (m, 4H), 7.39 (d, 1H), 7.47 (s,1H), 7.70 (q, 2H), 8.19 (d, 1H), 8.47 (d, 1H).

[0287] LRMS: m/z (TSP⁺) 471.1, 473.1 [MH⁺]

[0288] Microanalysis found: C, 58.74; H, 5.14; N, 11.28.C₂₄H₂₄Cl₂N₄O₂;0.3CH₂Cl₂ requires C, 58.74; H, 4.99; N, 11.28%.

EXAMPLES 113 TO 118

[0289] The following examples of general structure:

[0290] were prepared from the aldehyde from preparation 11b and theappropriate amines, following a similar procedure to that described inexample 112. Yield Example R (%) Data 113^(a)

43 clear oil ¹Hnmr (CDCl₃, 400MHz) δ: 1.82-2.32(m, 10H), 2.39(m, 2H),2.56(m, 1H), 3.22(s, 3H), 3.30(m, 2H), 3.88(d, 1H), 4.52(d, 1H), 7.10(m,1H), 7.19(d, 1H), 7.38(d, 1H), 7.43(s, 1H), 7.66(s, 2H), 8.43(d, 1H).LRMS: m/z (TSP⁺) 436.1, 438.1 [MH⁺]Microanalysis found: C, 60.17; H,6.24; N, 9.48. C₂₂H₂₇Cl₂N₃O₂requires C, 60.55; H, 6.24; N, 9.63%.114^(b)

42 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.62(m, 2H), 1.72(m, 1H), 1.84(m,1H), 2.00(s, 3H), 2.10(m, 6H), 2.30(m, 4H), 2.55-2.75(m, 4H), 2.91(t,1H), 3.41(t, 2H), 3.88(d, 1H), 4.54(d, 1H), 5.45(s, 1H), 7.17(m, 1H),7.21(m, 2H), 7.30(m, 2H), 7.37(m, 2H), 7.40(d, 1H), 7.45(s, 1H), 7.70(s,2H), 8.50(d, 1H). LRMS: m/z (TSP⁺) 620.3, 622.3 [MH⁺] 115^(c)

48 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.80(d, 2H), 2.00(m, 4H), 2.13(q,2H), 2.21(m, 2H), 2.33(dd, 2H), 2.46(m, 2H), 2.60(s, 3H), 2.93(d, 1H),3.01(d, 1H), 4.00(d, 1H), 4.09(m, 1H), 4.75(d, 1H), 7.18(m, 3H), 7.28(d,1H), 7.45(d, 1H), 7.46(d, 1H), 7.53(s, 1H), 7.68(d, 1H), 7.75(d, 2H),8.50(d, 1H) LRMS: m/z (TSP⁺) 562.1, 564.1 [MH⁺]Microanalysis found: C,62.70; H, 5.64; N, # 11.92. C₃₁H₃₃Cl₂N₅O; 0.18CH₂Cl₂ requires C, 62.88;H, 5.69; N, 11.66%. 116^(d)

79 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.78(d, 2H), 2.00(m, 4H), 2.07(m,1H), 2.19(q, 2H), 2.32(m, 4H), 2.61(m, 1H), 2.90(m, 2H), 3.99(d, 1H),4.30(m, 1H), 4.70(d, 1H), 7.05(s, 3H), 7.18(m, 2H), 7.43(d, 1H), 7.50(s,1H), 7.72(s, 2H), 8.50(d, 1H), 8.62(s, 1H). LRMS: m/z (TSP⁺) 564.1,566.1 [MH⁺]Microanalysis found: C, 59.45; H, 5.34; N, 11.39.C₃₀H₃₁Cl₂N₅O₂; # 0.6CH₂Cl₂ requires C, 59.72; H, 5.27; N, 11.38%.117^(e)

16 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.73-1.85(m, 3H), 1.85-1.97(m,3H), 1.97-2.06(m, 3H), 2.06-2.20(m, 2H), 2.28(m, 2H), 2.55(m, 1H),2.80(m, 3H), 3.90(d, 1H), 4.41(d, 1H), 7.09(m, 1H), 7.18(m, 3H), 7.20(s,1H), 7.38(d, 1H), 7.46(s, 1H), 7.65(m, 3H), 8.43(d, 1H), 9.33(bs, 1H).LRMS: m/z (TSP⁺) 548.1, 550.1 [MH⁺]Microanalysis found: C, 63.76; H,5.85; N, # 11.99. C₃₀H₃₁Cl₂N₅O; 0.25CH₂Cl₂ requires C, 63.77; H, 5.57;N, 12.29%. 118^(f)

66 white foam ¹Hnmr (CDCl₃, 400MHz) δ: 1.85-2.05(m, 11H), 2.30(m, 2H),2.59(dd, 1H), 2.75-2.95(m, 3H), 3.94(d, 1H), 4.70(d, 1H), 7.12(dd, 1H),7.23(d, 1H), 7.29(d, 2H), 7.41(d, 1H), 7.49(d, 1H), 7.50(s, 1H), 7.70(m,3H), 8.50(d, 1H). LRMS: m/z (TSP⁺) 549.2, 551.1 [MH⁺]Microanalysisfound: C, 64.55; H, 5.49; N, 9.89. C₃₀H₃₀Cl₂N₄O₂; # 0.06CH₂Cl₂ requiresC, 64.41; H, 5.43; N, 9.96%.

EXAMPLE 119(5S)-5-(3,4-Dichlorophenyl)-1-(6-methoxy-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0291]

[0292] The title compound was obtained as a white foam in 80% yield fromthe aldehyde from preparation 18 and 3-morpholinoazetidinedihydrochloride (WO 9725322), following the procedure described inexample 112.

[0293]¹Hnmr (CDCl₃, 400 MHz) δ: 1.68 (m, 2H), 1.79 (m, 1H), 2.05 (m,2H), 2.21 (m, 6H), 2.50 (m, 1H), 2.65 (m, 2H), 2.85 (m, 1H), 3.34 (q,2H), 3.65 (m, 4H), 3.73 (d, 1H), 3.96 (s, 3H), 4.59 (d, 1H), 6.58 (d,1H), 7.21 (d, 2H), 7.39 (d, 1H), 7.55 (s, 1H), 7.59 (dd, 1H).

[0294] LRMS: m/z (TSP⁺) 519.4, 521.4 [MH⁺]

[0295] Microanalysis found: C, 58.97; H, 6.18; N, 10.47.C₂₆H₃₂Cl₂N₄O₃;0.15CH₂Cl₂ requires C, 59.02; H, 6.12; N, 10.53%.

EXAMPLE 120N-(1-12-[(3S)-3-(3,4-Dichlorophenyl)-1-(6-methoxy-2-pyridinyl)-6-oxopiperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide

[0296]

[0297] The title compound was obtained as a white foam in 63% yield fromthe aldehyde from preparation 18 and N-methyl-N-(4-piperidinyl)acetamidehydrochloride from preparation 60 following the procedure described inexample 112.

[0298]¹Hnmr (CDCl₃, 400 MHz) δ: 1.50 (m, 4H), 1.80-2.20 (m, 7H), 2.05(s, 3H), 2.28 (m, 2H), 2.55 (m, 1H), 2.78 (2×s, 3H), 2.80 (m, 2H), 3.41,4.39 (2×m, 1H), 3.81 (m, 1H), 3.97 (s, 3H), 4.65 (d, 1H), 6.60 (d, 1H),7.25 (m, 2H), 7.41 (m, 1H), 7.60 (m, 2H).

[0299] LRMS: m/z (TSP⁺) 533.4, 535.4 [MH⁺]

[0300] Microanalysis found: C, 59.50; H, 6.38; N, 10.16.C₂₇H₃₄Cl₂N₄O₃;0.18CH₂Cl₂ requires C, 59.49; H, 6.31; N, 10.21%.

EXAMPLE 121(5S)-5-(3,4-Dichlorophenyl)-5-{2-[(3R)-3-methoxyprrolidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone

[0301]

[0302] Triethylamine (0.1 ml, 1.6 mmol) was added to a solution of thealdehyde hydrochloride from preparation 11b (200 mg, 0.5 mmol) indichloromethane (4 ml), followed by (3R)-3-methoxypyrrolidinetrifluoroacetate from preparation 47 (186 mg, 0.7 mmol), and thesolution stirred at room temperature for 10 minutes. Sodiumtriacetoxyborohydride (159 mg, 0.75 mmol) and acetic acid (60 μl, 2mmol) were added, and the reaction stirred at room temperature for 18hours. Methanol was added, the mixture stirred for 10 minutes, thenconcentrated under reduced pressure. The residue was partitioned betweensodium carbonate solution and dichloromethane, the layers separated, andthe organic phase evaporated under reduced pressure, to afford the titlecompound as a white gum, 199 mg.

[0303]¹Hnmr (CDCl₃, 400 MHz) δ: 1.74 (m, 1H), 1.84-2.00 (m, 3H), 2.10(m, 2H), 2.25 (m, 4H), 2.44 (m, 1H), 2.55 (m, 3H), 3.20 (s, 3H), 3.80(m, 1H), 4.10 (d, 1H), 4.54 (d, 1H), 7.08 (m, 1H), 7.19 (d, 1H), 7.39(d, 1H), 7.42 (s, 1H), 7.65 (d, 2H), 8.46 (d, 1H).

[0304] LRMS: m/z (TSP⁺) 448.0, 449.9 [MH⁺]

EXAMPLE 122(5S)-5-(3,4-Dichlorophenyl)-5-{2-[(3S)-3-methoxypyrrolidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone

[0305]

[0306] The title compound was obtained as a clear gum, in 85% yield fromthe aldehyde hydrochloride from preparation 11b and(3S)-3-methoxypyrrolidine trifluoroacetate from preparation 48,following the procedure described in example 121.

[0307]¹Hnmr (CDCl₃, 400 MHz) δ: 1.74 (m, 1H), 1.82-2.16 (m, 5H), 2.23(m, 4H), 2.44 (m, 1H), 2.52 (m, 3H), 3.20 (s, 3H), 3.80 (m, 1H), 3.88(d, 1H), 4.10 (d, 1H), 4.54 (d, 1H), 7.08 (m, 1H), 7.19 (d, 1H), 7.39(d, 1H), 7.42 (s, 1H), 7.65 (d, 2H), 8.46 (d, 1H).

[0308] LRMS: m/z (TSP⁺) 448.1, 450.1 [MH⁺]

EXAMPLE 123 tert-Butyl 4-{2-[(3S)-3-(3,4-dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-1-piperazinecarboxylate

[0309]

[0310] The title compound was obtained as a white foam in 73% yield fromthe aldehyde hydrochloride from preparation 11b and tert-butyl1-piperazinecarboxylate, following a similar procedure to that describedin example 121.

[0311]¹Hnmr (CDCl₃, 400 MHz) δ: 1.40 (s, 9H), 1.90 (m, 2H), 1.98 (m,1H), 2.04-2.34 (m, 8H), 2.56 (m, 1H), 3.30 (m, 4H), 3.92 (d, 1H), 4.62(d, 1H), 7.10 (m, 1H), 7.19 (d, 1H), 7.38 (d, 1H), 7.42 (s, 1H), 7.66(d, 2H), 8.44 (d, 1H).

[0312] LRMS: m/z (TSP⁺) 533.3 [MH⁺]

EXAMPLE 124(5S)-5-(3,4-Dichlorophenyl)-5-{2-[4-(2-methoxyethyl)-1-piperazinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone

[0313]

[0314] 1-(2-Methoxyethyl)piperazine hydrochloride (90 mg, 0.5 mmol),followed by triethylamine (100 mg, 1 mmol) were added to a solution ofthe aldehyde hydrochloride from preparation 11b (200 mg, 0.5 mmol) indichloromethane (2.5 ml), and stirring continued for 20 minutes. Aceticacid (50 mg, 0.83 mmol) and sodium triacetoxyborohydride (150 mg, 0.71mmol) were then added and the reaction stirred at room temperature for 1hour. Methanol (2 ml) was added, the mixture stirred for 20 minutes andthen evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using dichloromethane:methanol(93:7) as eluant. The product was redissolved in dichloromethane (10ml), washed with 10% aqueous potassium carbonate solution (3 ml), thendried (Na₂SO₄) and evaporated under reduced pressure, to afford thetitle compound as a clear foam, 180 mg.

[0315]¹Hnmr (CDCl₃, 400 MHz) δ: 1.88 (m, 2H), 1.99 (m, 1H), 2.10 (m,2H), 2.21-2.60 (m, 13H), 3.30 (s, 3H), 3.42 (t, 2H), 3.92 (d, 1H), 4.60(d, 1H), 7.10 (m, 1H), 7.18 (d, 1H), 7.37 (d, 1H), 7.42 (s, 1H), 7.64(m, 2H), 8.44 (m, 1H).

[0316] LRMS: m/z (ES⁺) 491 [MH⁺]

[0317] Microanalysis found: C, 61.10; H, 6.56; N, 11.40.C₂₅H₃₂Cl₂N₄O₂;0.5H₂O requires C, 60.00; H, 6.65; N, 11.19%.

EXAMPLE 125N-((3S)-1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}pyrrolidinyl)-N-methylacetamide

[0318]

[0319] A mixture of the aldehyde from preparation 11a (200 mg, 0.5mmol), the amine from preparation 44 (256 mg, 1.0 mmol), triethylamine(0.21 ml, 1.5 mmol), acetic acid (0.12 ml, 1.55 mmol) and sodiumtriacetoxyborohydride (211 mg, 1.0 mmol) in dichloromethane (50 ml) werestirred at room temperature in a STEM® block, for 24 hours. The mixturewas washed with aqueous sodium bicarbonate solution and water, theorganic layer filtered, dried (MgSO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (95:5:1) aseluant, to give the title compound.

[0320]¹Hnmr (CDCl₃, 400 MHz) δ: 1.58 (m, 2H), 1.90-2.70 (m, 17H), 2.96(m, 2H), 3.96 (d, 1H), 4.62 (m, 1H), 7.16 (d, 1H), 7.24 (m, 1H), 7.42(d, 1H), 7.50 (s, 1H), 7.74 (s, 2H), 8.50 (d, 1H).

[0321] LRMS: m/z (TSP⁺) 489.1, 491.2 [MH⁺]

EXAMPLES 126 TO 130

[0322] The following compounds of general formula:

[0323] were prepared from the appropriate aldehydes and amines,according to the procedure described in example 125. Example R¹ R² Data126^(a)

H ¹Hnmr (CDCl₃, 400 MHz) δ: 1.53-1.80 (m, 2H), 1.90-2.60 (m, 15H), 2.78(m, 1H), 2.92 (m, 2H), 3.92 (d, 1H), 4.36, 5.20 (2xs, 1H), 4.62 (m, 1H),7.12 (m, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.45 (s, 1H), 7.72 (m, 2H),8.48 (d, 1H). LRMS: m/z (TSP⁺) 489.1, 491.1 [MH⁺]Microanalysis found: C,60.32; H, 6.11; N, 11.25. C₂₅H₃₀Cl₂N₄O₂; # 0.5 H₂O requires C, 60.24; H,6.27; N, 11.24%. 127^(1b)

H ¹Hnmr (CDCl₃, 400 MHz) δ: 1.90-2.40 (m, 15H), 2.58 (m, 2H), 2.80 (m,1H), 3.36 (m, 2H), 3.94 (d, 1H), 4.64 (m, 2H), 7.16 (m, 1H), 7.20 (d,1H), 7.42 (d, 1H), 7.48 (s, 1H), 7.70 (m, 2H), 8.48 (d, 1H). LRMS: m/z(TSP⁺) 501.1, 503.2 [MH⁺]Microanalysis found: C, 60.68; H, 6.16; N,10.68. C₂₆H₃₀Cl₂N₄O₂: 0.2 CH₂Cl₂requires # C, 60.70; H, 5.91; N, 10.81%.128^(1c)

H ¹Hnmr (CDCl₃, 400 MHz) δ: 1.70-2.70 (m, 18H), 3.38 (m, 2H), 3.92 (d,1H), 4.62 (d, 1H), 4.70 (bs, 1H), 7.16 (dd, 1H), 7.20 (d, 1H), 7.42 (d,1H), 7.48 (s, 1H), 7.70 (m, 2H), 8.48 (d, 1H). LRMS: m/z (TSP⁺) 501.1,503.1 [MH⁺]Microanalysis found: C, 60.74; H, 6.18; N, 10.79.C₂₆H₃₀Cl₂N₄O₂: 0.2CH₂Cl₂requires # C, 60.70; H, 5.91; N, 10.81%. 129^(d)

CH₃ ¹Hnmr (CDCl₃, 400 MHz) δ: 1.70-2.80 (m, 22H), 2.90 (s, 2H), 3.90 (m,1H), 4.58 (dd, 1H), 7.00 (d, 1H), 7.20 (d, 1H), 7.40 (m, 2H), 7.58 (m,2H). LRMS: m/z (TSP⁺) 503.1 [MH⁺] 130^(e)

CH₃ ¹Hnmr (CDCl₃, 400 MHz) δ: 1.90-2.80 (m, 22H), 2.90 (m, 2H), 4.88 (d,1H), 4.34, 5.20 (2xbs, 1H), 7.00 (d, 1H), 7.22 (d, 1H), 7.40 (m, 2H),7.60 (m, 2H). LRMS: m/z (TSP⁺) 503.2 [MH⁺]Microanalysis found: C, 60.28;H, 6.69; N, 10.99. C₂₆H₃₂Cl₂N₄O₂; 0.2CH₂Cl₂requires C, 60.46; H, 6.27;N, 10.76%

EXAMPLE 131(5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0324]

[0325] A mixture of the aldehyde from preparation 12a (2.0 g, 5.3 mmol),3-morpholinoazetidine dihydrochloride (WO 9725322) (1.25 g, 5.83 mmol),triethylamine (1.84 ml, 13.3 mmol) and titanium isopropoxide (16 ml, 53mmol) in ethanol (20 ml), was stirred at room temperature for 18 hours.Sodium borohydride (320 mg, 7.95 mmol) in ethanol (19 ml) was then addedand the reaction stirred for 30 minutes. Sodium hydroxide was added, theresulting precipitate filtered off, and washed with ethyl acetate. Thefiltrate was washed with water (2×) and brine (2×), dried (MgSO₄) andevaporated under reduced pressure. The residual gum was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 99:1) to afford the title compound asa white solid, 1.58 g.

[0326]¹Hnmr (CDCl₃, 400 MHz) δ: 1.72 (m, 1H), 1.82 (m, 1H), 2.14 (m,2H), 2.24 (m, 7H), 2.56 (m, 1H), 2.58 (s, 3H), 2.75 (m, 2H), 2.90 (m,1H), 3.40 (m, 2H), 3.65 (m, 4H), 3.88 (d, 1H), 4.50 (d, 1H), 7.00 (d,1H), 7.20 (d, 1H), 7.40 (d, 2H), 7.55 (s, 1H), 7.60 (dd, 1H).

[0327] LRMS m/z (TSP⁺) 503.6, 505.2 [MH⁺]

EXAMPLES 132 TO 134

[0328] The compounds of the general structure:

[0329] were prepared from the aldehyde from preparation 12a and theappropriate amines, following a similar procedure to that described inexample 131. Yield Example R (%) Data 132^(a)

21 white solid ¹Hnmr (CDCl₃, 400 MHz) δ: 1.10-1.90 (m, 9H), 2.10 (m,3H), 2.25 (m, 3H), 2.56 (s, 3H), 2.56 (m, 3H), 2.74 (s, 3H), 3.28 (m,2H), 3.75 (d, 2H), 3.84 (d, 1H), 4.50 (d, 1H), 6.98 (d, 1H), 7.20 (d,1H), 7.28 (d, 1H), 7.40 (dd, 1H), 7.55 (m, 2H). LRMS : m/z (TSP⁺) 580.1,582.1 [MH⁺] 133^(b)

¹Hnmr (CDCl₃, 400 MHz) δ: 1.80 (m, 1H), 2.10-2.40 (m, 11H), 2.55 (s,4H), 2.75 (m, 5H), 2.94 (m, 1H), 3.20 (m, 4H), 3.40 (d, 1H), 3.88 (d,1H), 4.64 (d, 1H), 7.00 (d, 1H), 7.20 (d, 1H), 7.40 (d, 2H), 7.54 (s,1H), 7.60 (dd, 1H). LRMS: m/z (ES⁺) 580, 582 [MH⁺] 134^(1c)

9 white solid ¹Hnmr (CDCl₃, 400 MHz) δ: 1.50-2.60 (m, 20H), 3.95 (d,1H), 4.62 (d, 1H), 7.00 (d, 1H), 7.25 (d, 2H), 7.35 (d, 2H), 7.42 (m,4H), 7.60 (dd, 2H). LRMS: m/z (TSP⁺) 538.4 [MH⁺]Microanalysis found: C,64.82; H, 6.11; N, 7.49. C₃₀H₃₃Cl₂N₃O₂; 0.1 (CH₂CH₂)₂O; 0.9H₂O requiresC, 66.91; H, 6.18; N, 7.80%.

EXAMPLE 135a(5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-hydroxypiperidinyl)azetidinyl]ethyl}-2-piperidinone

[0330]

[0331] 3-(4-hydroxypiperidinyl)azetidine trifluoroacetate (WO96/05193—preparation 77)(25.2 gm, 65 mmol) was dissolved intetrahydrofuran (100 ml) and added to a solution of the aldehyde frompreparation 12a (24.8 gm, 65 mmol) in dichloromethane (300 ml). Sodiumtriacetoxyborohydride (21 gm, 98 mmol) was added and the reactionstirred at room temperature for 18 hours. The reaction was concentratedunder reduced pressure and the resulting orange oil was dissolved inethyl acetate (500 ml), washed with 2N sodium hydroxide solution (200ml), the aqueous layer extracted with ethyl acetate (2×200 ml), thecombined organic extracts were dried (MgSO₄), and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(90:10:1) as eluant to afford the title compound as a white foam (17gm).

[0332]¹Hnmr (CDCl₃, 400 MHz) δ: 1.52 (m, 3H), 1.70 (m, 1H), 1.85 (m,3H), 1.95 (m, 2H), 2.15 (m, 2H), 2.25 (m, 3H), 2.55 (m, 6H), 2.66 (m,2H), 2.86 (t, 1H), 3.42 (m, 2H), 3.70 (m, 1H), 3.84 (d, 1H), 4.50 (d,1H), 7.00 (d, 1H), 7.20 (d, 1H), 7.40 (dd, 2H), 7.58 (s, 1H), 7.60 (dd,1H).

[0333] LRMS: m/z (TSP⁺) 517.3 [MH⁺]

EXAMPLE 135b(5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-hydroxypiperidinyl)azetidinyl]ethyl}-2-piperidinonebisfumarate

[0334]

[0335] Fumaric acid (8 gm, 69 mmol) was dissolved in a mixture of water(3.4 ml, 190 mmol) and tetrahydrofuran (100 ml) before adding to asolution of the title compound from example 135a (24.7 gm, 47.7 mmol) intetrahydofuran (50 ml). Resulting solution was allowed to stand at roomtemperature for 1 hour, during which time a white precipitate hadformed. Mixture filtered, filter cake washed with tetrahydrofuran (30ml), diethyl ether (2×200 ml) and dried at 50° C. for 48 hours to give awhite solid (26.4 gm). Solid recrystallised from refluxing 2% (vol/vol)aqueous tetrahydrofuran (250 ml), upon cooling mixture filtered, filtercake washed with tetrahydofuran (2×100 ml), diethyl ether (3×500 ml) andair dried for 20 minutes. Resulting solid was slurried in acetone (100ml) for 18 hours, filtered washed with diethyl ether and dried for 48hours at 50° C. under reduced pressure (6 mbar) to give the titlecompound as a fine white solid.

[0336]¹Hnmr (CD₃OD, 400 MHz) δ: 1.54 (m, 2H), 1.82 (m, 2H), 1.94 (m,1H), 2.05 (m, 1H), 2.14 (m, 2H), 2.21 (m, 2H), 2.38 (m, 1H), 2.54 (m,4H), 2.66 (m, 2H), 2.73 (m, 1H), 2.94 (m, 1H), 3.25 (m, 1H), 3.65 (m,3H), 3.90 (d, 1H), 4.00 (m, 2H), 4.48 (d, 1H), 6.69 (s, 3H), 7.13 (d,1H), 7.25 (d, 1H), 7.44 (d, 1H), 7.54 (d, 1H), 7.68 (t, 1H), 7.81 (s,1H).

[0337] LRMS: m/z (TSP⁺) 517.3 [MH⁺]

[0338] Microanalysis found: C, 55.73; H, 5.67; N, 7.48.C₂₇H₃₄Cl₂N₄O₂;2.C₄H₄O₄;0.25H₂O requires C, 55.74; H, 5.68; N, 7.43%.

[0339] Mpt. 175.5-177° C.

EXAMPLE 136(5S)-5-(3,4-Dichlorophenyl)-1-(5-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0340]

[0341] The title compound was prepared as a yellow solid in 6% yieldfrom the aldehyde from preparation 14 and 3-morpholinoazetidinedihydrochloride (WO 9725322), following a similar procedure to thatdescribed in example 131, except ethyl acetate:pentane (10:90 to 100:0)was used as the column eluant.

[0342]¹Hnmr (CDCl₃, 400 MHz) δ: 1.75 (m, 1H), 1.85 (m, 1H), 2.20 (m,9H), 2.38 (s, 3H), 2.58 (m, 1H), 2.76 (m, 2H), 2.95 (m, 1H), 3.42 (m,2H), 3.68 (m, 4H), 3.90 (d, 1H), 4.50 (d, 1H), 7.12 (d, 1H), 7.42 (d,1H), 7.50 (s, 1H), 7.58 (m, 2H), 8.32 (s, 1H).

[0343] LRMS: m/z (TSP⁺) 503.3, 504.9 [MH⁺]

EXAMPLE 137(5S)-5-(3,4-Dichlorophenyl)-1-(6-ethyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0344]

[0345] The title compound was prepared as a white solid in 37% yield,from the aldehyde from preparation 16, and 3-morpholinoazetidinedihydrochloride (WO 9725322), following the procedure described inexample 131.

EXAMPLE 138N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(3-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide

[0346]

[0347] Potassium carbonate (390 mg, 2.82 mmol), copper (90 mg, 1.41mmol) and 3-bromopyridine (680 μl, 7.06 mmol) were added to the aminefrom preparation 83 (300 mg, 0.70 mmol) and the mixture stirred at 140°C. for 20 hours. The mixture was partitioned between water (100 ml) andethyl acetate (100 ml), and the layers separated. The aqueous phase wasextracted with ethyl acetate, the combined organic solutions washed withwater, then brine, and dried (Na₂SO₄) and evaporated under reducedpressure. The crude oil was purified by column chromatography on silicagel using an elution gradient of dichloromethane:methanol (95:5 to85:15) to afford the title compound as a yellow oil, 80 mg.

[0348]¹Hnmr (CDCl₃, 400 MHz) δ: 1.46 (m, 3H), 1.63 (m, 1H), 1.88 (m,3H), 2.00 (s, 3H), 2.20 (m, 1H), 2.37 (m, 2H), 2.58 (m, 1H), 2.75 (m,5H), 3.40 (s, 3H), 3.88 (d, 1H), 4.03 (m, 1H), 4.37 (m, 1H), 7.10 (d,1H), 7.30 (m, 2H), 7.40 (d, 1H), 7.60 (d, 1H), 8.45 (s, 1H), 8.53 (s,1H).

[0349] LRMS: m/z (ES⁺) 525, 527 [MH⁺]

[0350] Microanalysis found: C, 58.52; H, 6.18; N, 10.31.C₂₆H₃₂Cl₂N₄O₂;0.5CH₂Cl₂ requires C, 58.30; H, 6.09; N, 10.26%.

EXAMPLE 139N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-1-(6-methyl-3-pyridinyl)-6-oxopiperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide

[0351]

[0352] The title compound was obtained as a black solid in 71% yield,from the amine from preparation 83 and 5-bromo-2-methylpyridine,following a similar procedure to that described in example 138, except1-methyl-2-pyrrolidinone was used as the reaction solvent.

[0353]¹Hnmr (CD₃OD, 400 MHz) δ: 1.45 (m, 1H), 1.58 (m, 2H), 1.65 (m,1H), 1.85-2.14 (m, 10H), 2.24 (m, 2H), 2.42 (m, 1H), 2.56 (s, 3H), 2.74(s, 1H), 2.82 (m, 4H), 3.58 (m, 0.2H), 4.0 (d, 1H), 4.10 (d, 1H), 4.24(m, 0.8H), 7.38 (d, 2H), 7.57 (d, 1H), 7.60 (s, 1H), 7.63 (dd, 1H), 8.35(s, 1H).

[0354] LRMS: m/z (ES⁺) 539, 541 [MNa⁺]

[0355] Microanalysis found: C, 61.39; H, 6.59; N, 10.41.C₂₇H₃₄Cl₂N₄O₂;0.6H₂O requires C, 61.38; H, 6.72; N, 10.60%.

EXAMPLE 140N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyrazinyl)piperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide

[0356]

[0357] A mixture of the amine from preparation 83 (300 mg, 0.70 mmol),potassium tert-butoxide (160 mg, 1.43 mmol) and chloropyrazine (260 μl,2.8 mmol) in N-methylpyrrolidine (5 ml) was stirred at 100° C. for 72hours. The cooled mixture was partitioned between water (100 ml) andethyl acetate (100 ml), and the layers separated. The aqueous phase wasextracted with ethyl acetate, the combined organic solutions washed withwater and brine, then dried (MgSO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of dichloromethane:methanol:0.88ammonia (99:1:0.1 to 90:10:1) to afford the title compound as a brown,glass-like solid, 45 mg.

[0358]¹Hnmr (CDCl₃, 400 MHz) δ: 1.55 (m, 4H), 1.83-2.20 (m, 11H),2.26-2.43 (m, 2H), 2.60-2.82 (m, 5H), 3.92 (d, 1H), 4.38 (m, 1H), 4.64(d, 1H), 7.18 (d, 1H), 7.39 (d, 1H), 7.43 (s, 1H), 8.35 (s, 1H), 8.39(s, 1H), 9.19 (s, 1H).

[0359] LRMS: m/z (ES⁺) 526, 528 [MH⁺]

[0360] Microanalysis found: C, 52.88; H, 5.29; N, 12.27.C₂₅H₃₁Cl₂N₅O₂;CH₂Cl₂ requires C, 52.98; H, 5.64; N, 11.88%.

EXAMPLE 141N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyrazinyl)-6-oxopiperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide

[0361]

[0362] The title compound was obtained as a brown solid in 4% yield,from the amine from preparation 83 and 2-chloro-6-methylpyrazine(Tetrahedron 1972; 28; 4155), following a similar procedure to thatdescribed in example 140.

[0363]¹Hnmr (CDCl₃, 400 MHz) δ: 1.56 (m, 3H), 1.81-2.19 (m, 1H), 2.32(m, 2H), 2.58 (s, 3H), 2.62 (m, 1H), 2.80 (m, 5H), 3.40 (m, 0.2H), 3.85(dd, 1H), 4.42 (m, 0.8H), 4.58 (dd, 1H), 7.18 (d, 1H), 7.40 (d, 1H),7.50 (s, 1H), 8.22 (s, 1H), 8.86 (s, 1H).

[0364] LRMS: m/z (ES⁺) 540, 542 [MNa⁺]

EXAMPLE 142(5S)-5-(3,4-Dichlorophenyl)-5-(2-{methyl[(1R)-1-phenylethyl]amino}ethyl)-1-(2-pyridinyl)-2-piperidinoneDihydrochloride

[0365]

[0366] Formaldehyde (75 μl, 37% aq, 0.92 mmol) was added to a solutionof the amine from example 37 (160 mg, 0.30 mmol) in dichloromethane (25ml), and the solution stirred for 5 minutes. Sodiumtriacetoxyborohydride (63 mg, 0.30 mmol) was added and the reactionstirred at room temperature for 18 hours. Tlc analysis showed startingmaterial remaining, so additional formaldehyde (0.4 ml, 37% aq, 4.93mmol) and sodium triacetoxyborohydride (62 mg, 0.29 mmol) were added,and the reaction stirred for an hour. The reaction was washed withsaturated aqueous sodium bicarbonate solution (25 ml), brine (10 ml),dried (MgSO₄) and concentrated under reduced pressure. The residual foamwas redissolved in dichloromethane (10 ml), and treated with 1N etherealhydrochloric acid (5 ml). This solution was then evaporated underreduced pressure, to afford the title compound as a white foam, 158 mg.

[0367]¹Hnmr (CD₃OD, 400 MHz) δ: 1.63 (t, 3H), 2.06-3.00 (m, 11H),4.04-4.65 (m, 3H), 7.07-7.73 (m, 9H), 7.90 (m, 1H), 8.40 (m, 1H), 8.59(m, 1H).

[0368] LRMS: m/z (TSP⁺) 482.1, 484.1 [MH⁺]

EXAMPLE 143 (5S)-5-(3,4-Dichlorophenyl)-5-(2-{methyl[(1S)-1-phenylethyl]amino}ethyl)-1-(2-pyridinyl)-2-piperidinoneDihydrochloride

[0369]

[0370] The title compound was prepared in 91% yield from the amine fromexample 38, following the procedure described in example 142.

[0371]¹Hnmr (CD₃OD, 400 MHz) δ: 1.63 (t, 3H), 2.08-2.97 (m, 11H),4.10-4.23 (m, 1H), 4.28 (m, 0.5H), 4.41 (m, 1H), 4.60 (m, 0.5H),7.18-7.63 (m, 8H), 7.72 (dd, 1H), 7.92 (dd, 1H), 8.44 (dd, 1H), 8.60 (m,1H).

[0372] LRMS: m/z (TSP⁺) 482.1, 484.1 [MH⁺]

EXAMPLE 144(5S)-5-(3,4-Dichlorophenyl)-5-(2-{methyl[(1R)-1-phenylethyl]amino}ethyl)-1-(6-methyl-2-pyridinyl)-2-piperidinoneDihydrochloride

[0373]

[0374] The title compound was prepared from the amine from example 41 asa white solid, following a similar procedure to that described inexample 143.

[0375]¹Hnmr (CD₃OD, 400 MHz) δ: 1.63 (t, 3H), 2.07-2.97 (m, 14H), 4.08(d, 1H), 4.22 (q, 1H), 4.37 (m, 1H), 7.16-7.75 (m, 10H), 8.25-8.40 (m,1H).

[0376] LRMS: m/z (TSP⁺) 496.1, 498.2 [MH⁺]

[0377] Microanalysis found: C, 53.27; H, 6.15; N, 6.51.C₂₈H₃₁Cl₂N₃0;2HCl;3.5H₂O requires C, 53.18; H, 5.90; N, 6.64%

EXAMPLE 145(5S)-5-(3,4-Dichlorophenyl)-5-(2-{methyl[3-(4-morpholinyl)propyl]amino}ethyl)-1-(2-pyridinyl)-2-piperidinoneTrihydrochloride

[0378]

[0379] Triethylamine (0.5 ml) was added to a suspension of the aminefrom example 36 (267 mg, 0.44 mmol) in dichloromethane (20 ml), followedby acetic acid (0.5 ml), formaldehyde (0.36 ml, 4.44 mmol) and finallysodium triacetoxyborohydride (94.6 mg, 0.45 mmol), and the reactionstirred at room temperature for 2 hours. The mixture was washed withsaturated aqueous sodium bicarbonate solution (50 ml), brine (25 ml),dried (MgSO₄) and concentrated under reduced pressure. The crude productwas redissolved in dichloromethane, 1N ethereal hydrochloric acid addedand the solution then evaporated under reduced pressure to afford thetitle compound as a white foam, 258 mg.

[0380]¹Hnmr (CD₃OD, 400 MHz) δ: 2.22 (m, 2H), 2.32-2.59 (m, 6H),2.78-2.90 (m, 5H), 3.10-3.20 (m, 5H), 3.23 (m, 1H), 3.52 (m, 2H), 3.86(m, 2H), 4.14 (d, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.46 (d, 1H), 7.60(d, 1H), 7.65 (s, 1H), 7.80 (m, 1H), 8.15 (m, 1H), 8.04-8.56 (m, 2H).

EXAMPLE 146(5S)-5-(3,4-Dichlorophenyl)-5-{2-[methyl(2-pyridinylmethyl)amino]ethyl}-1-(2-pyridinyl)-2-piperidinoneTrihydrochloride

[0381]

[0382] The title compound was prepared as a white foam in 90% yield fromthe amine from example 56, following the procedure described in example145.

[0383]¹Hnmr (CD₃OD, 400 MHz) δ: 2.30-2.60 (m, 5H), 2.81 (m, 1H), 2.90(s, 3H), 2,98 (m, 1H), 3,17 (m, 1H), 4,30 (d, 1H), 4,41 (d, 1H), 4.58(s, 2H), 7,40 (d, 1H), 7.57 (d, 1H), 7.64 (m, 2H), 7.72 (d, 1H), 7.82(dd, 1H), 8.08 (m, 2H), 8.62 (m, 3H).

[0384] LRMS: m/z (TSP⁺) 471.1, 473.1 [MH⁺]

[0385] Microanalysis found: C, 43.15; H, 5.29; N, 7.64%.C₂₅H₂₆Cl₂N₄0;3HCl;3.5H₂O;CH₂Cl₂ requires C, 42.96; H, 5.27; N, 7.71%.

EXAMPLE 147(5S)-5-{2-[3-(4-Amino-1-piperidinyl)-1-azetidinyl]ethyl}-5-(3,4-dichlorophenyl)-1-(2-pyridinyl)-2-piperidinone

[0386]

[0387] Trifluoroacetic acid (10 ml) was added to an ice-cooled solutionof the protected amine from preparation 84 (760 mg, 1.26 mmol) indichloromethane (5 ml), and the solution stirred at 0° C. for 2 hours.The solution was poured into ice-cooled water (200 ml), basified using2N sodium hydroxide solution, and extracted with dichloromethane (3×200ml). The combined organic solutions were washed with brine, dried(MgSO₄), and evaporated under reduced pressure to give the titlecompound as a white foam, 540 mg.

[0388]¹Hnmr (CDCl₃, 300 MHz) δ: 1.34 (m, 2H), 1.81 (m, 8H), 2.13 (m,2H), 2.30 (m, 3H), 2.52-2.75 (m, 6H), 2.87 (m, 1H), 3.42 (m, 2H), 3.90(d, 1H), 4.56 (d, 1H), 7.20 (m, 2H), 7.43 (m, 2H), 7.72 (m, 2H), 8.52(d, 1H).

[0389] LRMS: m/z (ES⁺) 502, 504 [MH⁺]

EXAMPLE 148(5S)-5-(3,4-Dichlorophenyl)-5-[2-(1-piperazinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0390]

[0391] A solution of the protected amine from example 123 (923 mg, 1.78mmol) in 4M HCl in dioxan (50 ml) was stirred at room temperature for 18hours. The reaction mixture was concentrated under reduced pressure andthe residue partitioned between sodium bicarbonate solution anddichloromethane. The layers were separated, the organic phase dried(MgSO₄) and evaporated under reduced pressure to give a yellow solid,831 mg.

[0392] A sample (50 mg) was purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (90:10:1) as eluant toafford the title compound as a clear oil.

[0393]¹Hnmr (CDCl₃, 400 MHz) δ: 1.83-2.16 (m, 6H), 2.23 (m, 5H), 2.58(m, 1H), 2.89 (m, 4H), 3.89 (d, 1H), 4.60 (d, 1H), 7.12 (s, 1H), 7.19(d, 1H), 7.38 (d, 1H), 7.44 (s, 1H), 7.68 (s, 2H), 8.45 (d, 1H).

[0394] LRMS: m/z (TSP⁺) 433.1, 43.1 [MH⁺]

EXAMPLE 149(5S)-5-[2-(4-Amino-1-piperidinyl)ethyl]-5-(3,4-dichlorophenyl)-1-(2-pyridinyl)-2-piperidinone

[0395]

[0396] A solution of the protected amine from example 54 (577 mg, 1.05mmol) in 4M HCl in dioxan (10 ml) was stirred at room temperature for 2hours. The mixture was evaporated under reduced pressure and the residuepartitioned between 10% aqueous sodium carbonate solution and diethylether, and the layers separated. The aqueous phase was extracted withdiethyl ether, then dichloromethane, the combined organic solutionsdried (MgSO₄) and evaporated under reduced pressure, to give the titlecompound as a white foam, 465 mg.

[0397]¹Hnmr (CDCl₃, 400 MHz) δ: 1.42 (m, 2H), 1.83-1.98 (m, 7H), 2.13(m, 2H), 2.29 (m, 2H), 2.59 (m, 1H), 2.73 (m, 3H), 3.05 (m, 2H), 3.91(d, 1H), 4.56 (d, 1H), 7.13 (dd, 1H), 7.21 (d, 1H), 7.40 (d, 1H), 7.46(s, 1H), 7.68 (m, 2H), 8.48 (d, 1H).

[0398] LRMS: m/z (TSP⁺) 447.1, 449.1 [MH⁺]

EXAMPLE 150(5S)-5-(3,4-Dichlorophenyl)-5-{2-[4-(methylamino)-1-piperidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinoneDihydrochloride

[0399]

[0400] Hydrogen chloride was bubbled through a solution of the protectedamine from example 99 (340 mg, 0.607 mmol) in dichloromethane (50 ml)for 5 minutes. The mixture was evaporated under reduced pressure toafford a quantitative amount of the title compound as a white foam.

[0401]¹Hnmr (CD₃OD, 400 MHz) δ: 1.98 (m, 2H), 1.98-2.58 (m, 8H), 2.70(s, 3H), 2.81 (m, 2H), 3.00 (m, 2H), 3.38 (m, 2H), 3.62 (m, 2H), 4.22(d, 1H), 4.39 (d, 1H), 7.41 (m, 1H), 7.58 (d, 1H), 7.66 (s, 1H), 7.78(m, 1H), 8.02 (d, 1H), 8.58 (m, 1H).

[0402] LRMS: m/z (TSP⁺)461.1, 463.1 [MH⁺]

EXAMPLE 151N-[1-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-3-azetidinyl)-4-piperidinyl]acetamide

[0403]

[0404] Triethylamine (85 mg, 0.84 mmol) and acetic anhydride (74 mg,0.63 mmol) were added to a solution of the amine from example 147 (210mg, 0.42 mmol) in dichloromethane (100 ml), and the reaction stirred atroom temperature for 20 minutes. The solution was washed with 2N sodiumhydroxide solution, and the aqueous layer extracted with dichloromethane(2×50 ml). The combined organic solutions were dried (MgSO₄), evaporatedunder reduced pressure and the residue azeotroped with dichloromethane(4×200 ml), to afford the title compound as a white foam, 206 mg.

[0405]¹Hnmr (CDCl₃, 300 MHz) δ: 1.72-1.99 (m, 10H), 2.08-2.23 (m, 3H),2.23-2.42 (m, 3H), 2.54-2.69 (m, 3H), 2.78 (m, 2H), 2.93 (m, 1H), 3.49(m, 2H), 3.78 (m, 1H), 3.92 (d, 1H), 4.56 (d, 1H), 5.36 (m, 1H), 7.17(m, 1H), 7.21 (d, 1H), 7.44 (m, 2H), 7.74 (m, 2H), 8.51 (m, 1H).

[0406] LRMS: m/z (ES⁺) 544, 546 [MH⁺]

[0407] Microanalysis found: C, 57.75; H, 7.00; N, 11.80.C₂₈H₃₅Cl₂N₅O₂;2H₂O requires C, 57.93; H, 6.77; N, 12.06%.

EXAMPLE 152(5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-propionyl-1-piperazinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0408]

[0409] A mixture of the piperazine from example 148 (168 mg, 0.39 mmol),propionyl chloride (34 μl, 0.39 mmol) and triethylamine (54 μl, 0.39mmol) in dichloromethane (10 ml) was stirred at room temperature for anhour. The mixture was washed with water, and the aqueous solutionextracted with dichloromethane. The combined organic solutions weredried (MgSO₄) and evaporated under reduced pressure. The crude productwas purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to afford thetitle compound as a clear gum, 52 mg.

[0410]¹Hnmr (CDCl₃, 400 MHz) δ: 1.09 (t, 3H), 1.88 (d, 2H), 1.99 (s,1H), 2.13 (m, 2H), 2.23 (m, 8H), 2.58 (m, 1H), 3.33 (s, 2H), 3.50 (s,2H), 3.90 (d, 1H), 4.62 (d, 1H), 7.11 (s, 1H), 7.19 (d, 1H), 7.38 (d,1H), 7.43 (s, 1H), 7.68 (s, 2H), 8.42 (d, 1H).

[0411] LRMS: m/z (TSP⁺) 489.2, 491.2 [MH⁺]

EXAMPLES 153 TO 156

[0412] The following compounds of general formula:

[0413] were prepared from the piperazine from example 148 and theappropriate acid chloride, according to the method described in example152. Yield Example R (%) Data 153

42 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.97 (m, 2H), 2.03 (m, 1H), 2.18 (m, 2H),2.30 (m, 6H), 2.60 (m, 1H), 3.42 (s, 3H), 3.43 (s, 2H), 3.57 (s, 2H),3.98 (d, 1H), 4.08 (s, 2H), 4.68 (d, 1H), 7.18 (m, 1H), 7.23 (d, 1H),7.42 (d, 1H), 7.50 (s, 1H), 7.75 (s, 2H), 8.51 (d, 1H). LRMS: m/z (TSP⁺)505.1, 507.2 [MH⁺] 154

33 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.08 (d, 6H), 1.90-2.35 (m, 11H), 2.55 (s,1H), 3.33 (m, 4H), 3.86 (d, 1H), 4.60 (d, 1H), 4.82 (m, 1H), 7.08 (m,1H), 7.20 (d, 1H), 7.38 (d, 1H), 7.41 (s, 1H), 7.63 (s, 2H), 8.41 (s,1H). LRMS: m/z (TSP⁺) 519.2, 521.2 [MH⁺] 155

¹Hnmr (CDCl₃, 300 MHz) δ: 1.86-2.10 (m, 3H), 2.10-2.40 (m, 9H), 2.60 (m,1H), 2.81 (m, 6H), 3.19 (m, 3H), 3.97 (d, 1H), 4.64 (d, 1H), 7.12-7.32(m, 2H), 7.40 (d, 1H), 7.49 (s, 1H), 7.74 (m, 2H), 8.48 (d, 1H). LRMS:m/z (TSP⁺) 504.2, 506.2 [MH⁺] 156

24 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.11 (t, 6H), 1.90-2.40 (m, 11 H), 2.60 (m,1H), 3.19 (m, 8H), 3.97 (d, 1H), 4.68 (d, 1H), 7.18 (m, 1H), 7.22 (m,1H), 7.41 (d, 1H), 7.50 (s, 1H), 7.73 (d, 2H), 8.51 (d, 1H). LRMS: m/z(TSP⁺) 532.3, 534.2 [MH⁺]

EXAMPLE 157N′-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N,N-diethylurea

[0414]

[0415] Triethylamine (40 μl, 0.32 mmol) and diethylcarbamoyl chloride(40 μl, 0.30 mmol) were added to a solution of the amine from example149 (120 mg, 0.27 mmol) in tetrahydrofuran (5 ml), and the reactionstirred at 40° C. for 18 hours. The mixture was concentrated underreduced pressure and the residue purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (90:10:1) toafford the title compound, 129 mg.

[0416]¹Hnmr (CDCl₃, 400 MHz) δ: 1.11 (t, 6H), 1.27 (m, 2H), 1.96 (m,6H), 2.14 (m, 2H), 2.30 (m, 2H), 2.58 (m, 1H), 2.68 (d, 2H), 3.22 (q,4H), 3.62 (m, 1H), 3.92 (d, 1H), 4.06 (d, 1H), 4.61 (d, 1H), 7.14 (dd,1H), 7.22 (d, 1H), 7.40 (d, 1H), 7.48 (s, 1H), 7.70 (s, 2H), 8.48 (d,2H).

[0417] LRMS: m/z (ES⁺) 546, 548 [MH⁺]

EXAMPLE 158N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide

[0418]

[0419] The title compound was obtained as a white foam in 89% yield,from the amine from example 150 and acetyl chloride, following a similarprocedure to that described in example 157, except that dichloromethanewas used as the reaction solvent.

[0420]¹Hnmr (CDCl₃, 400 MHz) δ: (mixture of rotamers) 1.48 (m, 4H), 1.68(m, 1H), 1.88 (s, 3H), 1.97 (m, 1H), 2.02 (2×s, 3H), 2.11 (m, 2H), 2.26(m, 2H), 2.54 (m, 1H), 2.72 (s, 2H), 2.76 (s, 3H), 3.40, 4.36 (2×m, 1H),3.91 (d, 1H), 4.58 (d, 1H), 7.10 (dd, 1H), 7.19 (d, 1H), 7.37 (d, 1H),7.44 (s, 1H), 7.67 (s, 2H), 8.44 (s, 1H).

[0421] LRMS: m/z (ES⁺) 503, 505 [MH⁺]

[0422] Microanalysis found: C, 60.66; H, 6.55; N, 10.89.C₂₆H₃₂Cl₂N₄O₂;0.5H₂O requires C, 60.94; H, 6.49; N, 10.93%.

EXAMPLE 159N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N′,N′-diethyl-N-methylurea

[0423]

[0424] Triethylamine (55 μl, 0.40 mmol) and diethylcarbamoyl chlorde (50μl, 0.36 mmol) were added to a solution of the amine from example 150(152 mg, 0.33 mmol) in dichloromethane (5 ml), and the solution stirredat room temperature for 2 hours. Tlc analysis showed starting materialremaining, so additional diethylcarbamoyl chloride (50 μl, 0.36 mmol)was added and the reaction stirred at room temperature for 18 hours. Themixture was concentrated under reduced pressure and the residue purifiedby column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (90:10:1) as eluant, to afford thetitle compound as a white foam, 152 mg.

[0425]¹Hnmr (CDCl₃, 400 MHz) δ: 1.09 (t, 6H), 1.63 (m, 4H), 1.93 (m,5H), 2.12 (m, 2H), 2.30 (m, 2H), 2.58 (m, 1H), 2.66 (s, 3H), 2.80 (m,2H), 3.12 (q, 4H), 3.54 (m, 1H), 3.92 (d, 1H), 4.62 (d, 1H), 7.13 (dd,1H), 7.22 (d, 1H), 7.40 (d, 1H), 7.48 (s, 1H), 7.70 (s, 2H), 8.48 (dd,1H).

[0426] LRMS: m/z (ES⁺) 560, 562 [MH⁺]

[0427] Microanalysis found: C, 61.07; H, 7.04; N, 12.21.C₂₉H₃₉Cl₂N₅O₂:0.15CH₂Cl₂ requires C, 61.07; H, 6.91; N, 12.22%.

EXAMPLE 160N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)methanesulfonamide

[0428]

[0429] Triethylamine (43 μl, 0.31 mmol) and methanesulphonyl chloride(20 μl, 0.26 mmol) were added to an ice-cooled solution of the aminefrom example 149 (115 mg, 0.26 mmol) in dichloromethane (5 ml), and thesolution stirred at room temperature for an hour. The mixture was washedwith water, then brine, dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (90:10:1) to afford thetitle compound.

[0430]¹Hnmr (CDCl₃, 300 MHz) δ: 1.60 (m, 4H), 1.85-2.44 (m, 11H), 2.63(m, 1H), 2.80 (m, 1H), 2.99 (s, 3H), 3.32 (m, 1H), 3.97 (d, 1H), 4.65(d, 1H), 7.17 (m, 1H), 7.23 (d, 1H), 7.44 (d, 1H), 7.51 (s, 1H), 7.73(m, 2H), 8.50 (d, 1H).

[0431] LRMS: m/z (ES⁺) 525, 527 [MH⁺]

EXAMPLE 161N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)benzenesulfonamide

[0432]

[0433] The title compound was obtained, from the amine from example 149and phenylsulphonyl chloride, following the procedure described inexample 160.

[0434]¹Hnmr (CDCl₃, 400 MHz) δ: 1.33 (m, 3H), 1.47-2.17 (m, 8H),2.18-2.36 (m, 2H), 2.52 (m, 3H), 3.09 (bs, 1H), 3.86 (d, 1H), 4.35 (bs,1H), 4.60 (d, 1H), 7.10 (m, 1H), 7.18 (d, 1H), 7.28-7.59 (m, 5H), 7.66(s, 2H), 7.81 (m, 2H), 8.43 (d, 1H).

[0435] LRMS: m/z (TSP⁺) 587.2, 589.2 [MH⁺]

[0436] Microanalysis found: C, 57.25; H, 5.54; N, 8.84.C₂₉H₃₂Cl₂N₄O₃S;1.2H₂O requires C, 57.18; H, 5.69; N, 9.20%.

EXAMPLE 162N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N-methylmethanesulfonamide

[0437]

[0438] Triethylamine (0.21 ml, 1.51 mmol) followed by methanesulphonylchloride (0.1 ml, 1.28 mmol) were added to an ice-cooled solution of theamine from example 150 (340 mg, 0.6 mmol) in dichloromethane (10 ml) andthe reaction stirred at room temperature for 2 hours. The mixture waswashed with water, the aqueous wash extracted with dichloromethane andthe combined organic solutions washed with brine, dried (MgSO₄) andconcentrated under reduced pressure. The residual oil was purified bycolumn chromatography on silica gel using dichloromethane:methanol:0.88ammonia (95:5:0.5) as eluant to afford the title compound as a whitefoam, 102 mg.

[0439]¹Hnmr (CD₃Cl, 400 MHz) δ:1.50 (m, 4H), 1.60 (m, 2H), 1.80-2.18 (m,6H), 2.28 (m, 2H), 2.58 (m, 1H), 2.72 (m, 4H), 2.78 (s, 3H), 3.61 (m,1H), 3.95 (d, 1H), 4.59 (d, 1H), 7.10 (m, 1H), 7.20 (m, 1H), 7.39 (m,1H), 7.42 (s, 1H), 7.69 (m 2H), 8.43 (d, 1H).

[0440] LRMS m/z (TSP⁺) 539.1, 541.2 [MH⁺]

EXAMPLE 163N-[1-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-3-azetidinyl)-4-piperidinyl]methanesulfonamide

[0441]

[0442] Triethylamine (127 mg, 1.26 mmol) and methanesulphonyl chloride(120 mg, 1.05 mmol) were added to a solution of the amine from example147 (210 mg, 0.42 mmol) in dichloromethane (100 ml), and the reactionstirred for 20 minutes. The mixture was washed with 0.88 ammonia (20ml), the layers separated, and the aqueous phase was extracted withdichloromethane (2×100 ml). The combined organic solutions were washedwith brine, dried (MgSO₄), evaporated under reduced pressure andazeotroped with dichloromethane (4×100 ml), to afford the title compoundas a white foam, 210 mg.

[0443]¹Hnmr (CDCl₃, 400 MHz) δ: 1.56 (m, 2H), 1.87-2.04 (m, 5H),2.08-2.39 (m, 6H), 2.46 (m, 1H), 2.62 (m, 3H), 2.81-3.00 (m, 5H), 3.32(m, 1H), 3.60 (m, 2H), 3.92 (d, 1H), 4.57 (d, 1H), 4.67 (m, 1H), 7.16(m, 1H), 7.23 (d, 1H), 7.43 (m, 2H), 7.73 (m, 2H), 8.49 (m, 1H).

[0444] LRMS: m/z (ES⁺) 580, 582 [MH⁺]

EXAMPLE 1645-(3,4-Dichlorophenyl)-5-{2-[(2-phenoxyethyl)amino]ethyl}-1-(2-pyridinyl)-2-piperidinone

[0445]

[0446] Triethylamine was added to a suspension of 2-phenoxyethylamine indichloromethane (8 ml) until a solution was obtained, and thensufficient acetic acid was added to achieve a pH of 4. A solution of thealdehyde hydrochloride from preparation 11b (250 mg, 0.63 mmol) indichloromethane (5 ml) was added followed by sodiumtriacetoxyborohydride (132 mg, 0.63 mmol), and the reaction stirred for20 minutes. 4N Sodium hydroxide solution was added, the mixture stirredfor 30 minutes, then filtered through a phase separation membrane. Theorganic filtrate was concentrated under reduced pressure, and theresidue purified by column chromatography usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant. The productwas redissolved in dichloromethane, treated with 1N etherealhydrochloric acid, and the mixure evaporated under reduced pressure toafford the title compound as a white solid, 199 mg.

[0447]¹Hnmr (CD₃OD, 400 MHz) δ: 2.20-2.40 (m, 3H), 2.43-2.60 (m, 2H),2.73-2.92 (m, 2H), 2.90-3.05 (m, 1H), 3.40 (m, 2H), 4.15-4.27 (m, 3H),4.46 (d, 1H), 6.88-7.03 (m, 3H), 7.28 (dd, 2H), 7.44 (d, 1H), 7.59 (d,1H), 7.68-7.75 (m, 2H), 7.93 (d, 1H), 8.43 (dd, 1H), 8.60 (d, 1H).

[0448] LRMS: m/z (TSP⁺) 484.1, 486.1 [MH⁺]

EXAMPLES 165 TO 167

[0449] The following examples of general structure:

[0450] were prepared as white solids, from the aldehyde hydrochloridefrom preparation 11b and the appropriate amine, according to theprocedure described in example 164. Example R Yield Data 165^(a)

37 ¹Hnmr (CD₃OD, 400 MHz) δ: 2.17-2.38 (m, 3H), 2.40-2.57 (m, 2H),2.70-2.78 (m, 1H), 2.84 (m, 1H), 3.01 (m, 1H), 3.41 (t, 2H), 4.17 (d,1H), 4.26 (t, 2H), 4.50 (d, 1H), 6.97-7.16 (m, 4H), 7.45 (d, 1H),7.52-7.60 (m, 2H), 7.73 (d, 1H), 7.80 (d, 1H), 8.20 (dd, 1H), 8.58 (d,1H). LRMS: m/z (TSP⁺) 504.2, 506.2 [MH⁺] 166^(b)

39 ¹Hnmr (CD₃OD, 400 MHz) δ: 2.18-2.42 (m, 3H), 2.42-2.60 (m, 2H),2.72-2.89 (m, 2H), 2.95 (m, 1H), 3.37 (t, 2H), 4.15-4.36 (m, 3H), 4.43(d, 1H), 6.60-6.82 (m, 3H), 7.24 (dd, 1H), 7.40 (d, 1H), 7.52 (d, 1H),7.68 (d, 1H), 7.75 (dd, 1H), 7.99 (d, 1H), 8.50 (dd, 1H), 8.55 (d, 1H).Microanalysis found: C, 50.39; H, 5.26; N, 6.60. C₂₆H₂₆Cl₂FN₃O₂; 2HCl;# 2.5H₂O requires C, 49.78; H, 5.30: N, 6.70% 167^(c)

17 ¹Hnmr (CD₃OD, 400 MHz) δ: 2.21-2.46 (m, 3H), 2.46-2.61 (m, 2H),2.72-2.90 (m, 2H), 2.99 (m, 1H), 3.39 (t, 2H), 4.12-4.35 (m, 3H), 4.46(d, 1H), 6.93 (m, 2H), 7.02 (m, 2H), 7.46 (d, 1H), 7.60 (d, 1H), 7.74(s, 1H), 7.77 (dd, 1H), 8.01 (d, 1H), 8.51 (dd, 1H), 8.60 (d, 1H).Microanalysis found: C, 50.01; H, 5.36; N, 6.89. C₂₆H₂₆Cl₂FN₃O₂; 2HCl;# 2.5H₂O requires C, 49.78; H, 5.30; N, 6.70%.

EXAMPLE 1685-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-oxo-1-piperidinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0451]

[0452] Dess-Martin periodinane (165 mg, 0.39 mmol) was added to asolution of the alcohol from example 132 (200 mg, 0.386 mmol) indichloromethane (10 ml), and the solution stirred at room temperaturefor an hour. Tic analysis showed starting material remaining, soadditional Dess-Martin periodinane (82.5 mg, 0.19 mmol) was added andthe reaction stirred for a further 30 minutes. Sodium thiosulphate (100mg), and aqueous sodium bicarbonate solution (10 ml) were added, and themixture stirred for 10 minutes. The layers were separated, the organicphase dried (Na₂SO₄) and evaporated under reduced pressure. The residualgum was purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1)to afford the title compound as a white foam, 125 mg.

[0453]¹Hnmr (CD₃OD, 400 MHz) δ: 1.60-2.60 (m, 25H), 3.95 (d, 1H), 4.50(d, 1H), 7.00 (d, 1H), 7.24 (d, 1H), 7.44 (d, 2H), 7.60 (m, 2H).

[0454] LRMS: m/z (TSP⁺) 515.1, 517.2 [MH⁺]

EXAMPLE 169(5S)-5-(3,4-Dichlorophenyl)-1-(4-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0455]

[0456] The title compound was prepared as a yellow solid in 32% yieldfrom the aldehyde from preparation 15 and 3-morpholinoazetidinedihydrochloride (WO 9725322), following a similar procedure to thatdescribed in example 131.

[0457]¹Hnmr (CDCl₃, 400 MHz) δ:1.82 (m, 1H), 1.97 (m, 1H), 2.12 (m, 2H),2.18-2.27 (m, 10H), 2.57 (m, 2H), 2.88-3.10 (m, 3H), 3.63 (m, 5H), 3.88(d, 1H), 4.42 (d, 1H), 6.96 (d, 1H), 7.20 (m, 1H), 7.40 (m, 2H), 7.48(s, 1H), 8.30 (d, 1H).

[0458] LRMS: m/z (TSP⁺) 503.2, 504.9 [MH⁺]

EXAMPLE 170(5S)-5-(3,4-Dichlorophenyl)-1-(3-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0459]

[0460] The title compound was prepared as a yellow solid in 8% yieldfrom the aldehyde from preparation 13 and 3-morpholinoazetidinedihydrochloride (WO 9725322), following a similar procedure to thatdescribed in example 131.

[0461]¹Hnmr (CDCl₃, 400 MHz) δ: 1.72-1.92 (m, 2H), 2.01 (m, 2H),2.12-2.40 (m, 8H), 2.57 (m, 1H), 2.80 (m, 2H), 2.98 (m, 1H), 3.43 (m,3H), 3.70 (m, 5.5H), 3.90 (m, 0.5H), 4.22 (m, 0.5H), 4.42 (m, 0.5H),7.19 (m, 2H), 7.38 (m, 0.5H), 7.44 (m, 1H), 7.58 (m, 1H), 7.80 (m,0.5H), 8.40 (m, 1H).

[0462] LRMS: m/z (TSP⁺) 503.6, 505.7 [MH⁺]

EXAMPLE 171 (5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0463]

[0464] The title compound was prepared in 35% yield as a white foam,from the aldehyde hydrochloride from preparation 11b and1,2,3,6-tetrahydro-4-phenylpyridine, following a similar procedure tothat described in example 17.

[0465]¹Hnmr (CDCl₃, 400 MHz) δ: 1.98-2.38 (m, 7H), 2.50 (m, 2H), 2.58(m, 3H), 3.01 (s, 2H), 3.95 (d, 1H), 4.62 (d, 1H), 5.98 (s, 1H), 7.15(m, 1H), 7.20-7.38 (m, 7H), 7.40 (d, 1H), 7.52 (s, 1H), 7.72 (d, 2H),8.47 (d, 1H).

[0466] LRMS: m/z (TSP⁺) 506.1, 508.0 [MH⁺]

EXAMPLE 172(5S)-5-(3,4-Dichlorophenyl)-5-[2-(1,1-dioxido-4-thiomorpholinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0467]

[0468] The title compound was prepared in 83% yield as a white foam,from the aldehyde hydrochloride from preparation 11b and thiomorpholine1,1-dioxide (WO 9605193) following a similar procedure to that describedin example 17.

[0469]¹Hnmr (CDCl₃, 400 MHz) δ: 1.90 (t, 2H), 2.10-2.38 (m, 5H), 2.58(m, 1H), 2.78 (m,

[0470] 2H), 2.86 (m, 2H), 2.99 (m, 4H), 3.88 (d, 1H), 4.90 (d, 1H), 7.18(m, 2H), 7.41 (d, 1H), 7.45 (s, 1H), 7.72 (dd, 1H), 7.80 (d, 1H), 8.52(d, 1H).

[0471] LRMS: m/z (TSP⁺) 482.1, 484.1 [MH⁺]

[0472] Microanalysis found: C, 54.53; H, 5.31; N, 8.50. C₂₂H₂₅Cl₂N₃O₃Srequires C, 54.77; H, 5.22; N, 8.71%.

EXAMPLE 173(5S)-5-(3,4-Dichlorophenyl)-5-[2-(2,6-dimethyl-4-morpholinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone

[0473]

[0474] The title compound was prepared in 30% yield as a white foam,from the aldehyde hydrochloride from preparation 11b and2,6-dimethylmorpholine following a similar procedure to that describedin example 17.

[0475]¹Hnmr (CDCl₃, 400 MHz) δ: 1.06 (2×d, 6H), 1.55 (m, 2H), 1.92 (m,3H), 2.02-2.18 (m, 2H), 2.26 (m, 2H), 2.55 (m, 3H), 3.54 (m, 2H), 3.90(d, 1H), 4.58 (d, 1H), 7.11 (m, 1H), 7.19 (d, 1H), 7.38 (d, 1H), 7.42(s, 1H), 7.66 (m, 2H), 8.45 (m, 1H).

[0476] LRMS: m/z (ES⁺) 462, 464 [MH⁺]

EXAMPLE 174(5S)-5-{2-[3-(4-Amino-1-piperidinyl)-1-azetidinyl]ethyl}-5-(3,4-dichlorophenyl)-1-(6-methyl-2-pyridinyl)-2-piperidinoneTetratrifluoroacetate

[0477]

[0478] A mixture of the protected amine from preparation 85 (59 mg, 0.1mmol) and trifluoroacetic acid (0.5 ml) in dichloromethane (3 ml) wasstirred at room temperature for 1 hour. The mixture was concentratedunder reduced pressure, and the residue azeotroped with toluene (3×) anddiethyl ether to afford the title compound as a brown solid, 60 mg.

[0479]¹Hnmr (CD₃OD, 400 MHz) δ: 1.74 (m, 2H), 1.99-2.32 (m, 8H), 2.40(m, 1H), 2.58 (m, 5H), 2.84-3.30 (m, 6H), 3.53 (m, 1H), 3.98 (d, 1H),4.06 (m, 1H), 4.20 (m, 2H), 4.48 (d, 1H), 7.20 (d, 1H), 7.30 (d, 1H),7.45 (d, 1H), 7.60 (d, 1H), 7.78 (dd 1H), 7.83 (s, 1H).

[0480] Microanalysis found: C, 42.44; H, 4.38; N, 6.48.

[0481] C₂₇H₃₅Cl₂N₅0;4CF₃CO₂H;0.2(C₂H₅)₂O;1.5H₂O requires C, 42.39; H,4.37; N, 6.90%.

EXAMPLE 1755-(3,4-difluorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone

[0482]

[0483] The title compound was prepared as a white foam in 63% yield fromthe aldehyde from preparation 12c and 3-morpholinoazetidinedihydrochloride (WO 9725322), following a similar procedure to thatdescribed in example 112, except dichloromethane:methanol:0.88 ammonia(96:4:0.4) was used as the column eluant.

[0484]¹Hnmr (CDCl₃, 400 MHz) δ: 1.50-2.00 (m, 6H), 2.05-2.46 (m, 7H),2.58 (s, 3H), 2.80 (m, 1H), 2.95 (m, 1H), 3.44 (m, 2H), 3.64 (m, 4H),3.86 (d, 1H), 4.44 (d, 1H), 6.97(d, 1H), 7.12 (m, 2H), 7.24 (m, 1H),7.41 (d, 1H), 7.58 (t, 1H).

[0485] LRMS: m/z (TSP⁺) 471.3 [MH⁺]

[0486] Microanalysis found: C, 65.42; H, 6.90; N, 11.68. C₂₆H₃₂F₂N₄O₂;0.4H₂O; 0.1 Et₂O requires C, 65.36; H, 7.02; N, 11.55.

EXAMPLE 1765-(3,4-difluorophenyl)-5-{2-[4-hydroxy-4-phenyl-1-piperidinyl]ethyl}-1-(6-methyl-2-pyridinyl)-2-piperidinone

[0487]

[0488] The title compound was prepared as a white solid in 82% yieldfrom the aldehyde from preparation 12c and 4-hydroxy-4-phenylpiperidine,following a similar procedure to that described in example 1, exceptusing a elution gradient of dichloromethane:methanol:0.88 ammonia(97:3:0.3-96:4:0.4).

[0489]¹Hnmr (CDCl₃, 400 MHz) δ: 1.55 (m, 3H), 1.72 (m, 2H), 1.90-2.40(m, 10H), 2.44-2.80 (m, 5H), 3.94 (d, 1H), 4.61 (d, 1H), 6.99(d, 1H),7.15 (m, 2H), 7.27 (m, 1H), 7.36 (m, 3H), 7.44 (m, 3H), 7.60 (t, 1H).

[0490] LRMS: m/z (TSP⁺) 506.3 [MH⁺]

[0491] Microanalysis found: C, 69.78; H, 6.63; N, 8.13. C₃₀H₃₃F₂N₃O₂;0.3H₂O; 0.1 CH₂Cl₂ requires C, 69.59; H, 6.56; N, 8.09.

EXAMPLE 1775-(3,4-difluorophenyl)-5-{2-[1,4-dioxa-8-azaspiro[4.5]dec-8-yl]ethyl}-1-(6-methyl-2-pyridinyl)-2-piperidinone

[0492]

[0493] The title compound was prepared as a white foam in 69% yield fromthe aldehyde from preparation 12c and 1,4-dioxa-8-azaspiro[4.5]decane,following a similar procedure to that described in example 1, exceptusing a elution gradient of dichloromethane:methanol:0.88 ammonia(97:3:0.3-95:5:0.5).

[0494]¹Hnmr (CDCl₃, 400 MHz) δ: 1.40-2.80 (m, 19H), 3.92 (m, 5H), 4.60(m, 1H), 6.96 (d, 1H), 7.12 (m, 2H), 7.24 (m, 1H), 7.40 (d, 1H), 7.57(t, 1H).

[0495] LRMS: m/z (TSP⁺) 472.5 [MH⁺]

[0496] Microanalysis found: C, 65.35; H, 6.74; N, 8.70. C₂₆H₃₁F₂N₃O₃;0.4H₂O; 0.05 Et₂O requires C, 65.23; H, 6.75; N, 8.71.

Preparation 1(5S)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-1-(2-pyridinyl)-2-piperidinone

[0497]

[0498] Potassium tert-butoxide (68 g, 0.606 mol) was added to asuspension of(5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidinone(WO 9807722) (200 g, 0.606 mol) in 1,2-dimethoxyethane (700 ml), and themixture heated under reflux for 1 hour. 2-Fluoropyridine (59 g, 0.606mol) was then added and the mixture stirred under reflux for 1 hour.Additional potassium tert-butoxide (34 g, 0.303 mol) and2-fluoropyridine (30 g, 0.303 mol) were added and the reaction mixturestirred under reflux for a further hour. The cooled mixture waspartitioned with water (500 ml), and the aqueous layer then extractedwith ethyl acetate (2×500 ml). The combined organic extracts were dried(MgSO₄), and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel using an elutiongradient of ethyl acetate:pentane (20:80 to 100:0) to afford the titlecompound as a clear gum, 129 g.

[0499]¹Hnmr (CDCl₃, 300 MHz) δ: 1.98 (dd, 1H), 2.16-2.39 (m, 4H),2.55-2.70 (m, 1H), 3.68 (m, 2H), 3.85 (m, 2H), 3.98 (d, 1H), 4.43 (t,1H), 4.70 (d, 1H), 7.15 (dd, 1H), 7.29 (dd, 1H), 7.42 (d, 1H), 7.53 (s,1H), 7.65 (m, 2H), 8.52 (d, 1H).

[0500] LRMS: m/z (TSP⁺) 407.2, 409.5 [MH⁺]

Preparation 2 (5S)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-1-(6-methyl-2-pyridinyl)-2-piperidinone

[0501]

[0502] A mixture of(5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidinone(WO 9807722) (6.5 g, 19.7 mmol), potassium carbonate (3.05 g, 21.7mmol), copper (I) iodide (400 mg, 2.1 mmol) and 2-bromo-6-methylpyridine(10.2 g, 60 mmol) in 1-methyl-2-pyrrolidinone (200 ml) was stirred at140° C. for 24 hours. The cooled mixture was partitioned between ethylacetate and 10% aqueous ammonia, and the layers separated. The aqueousphase was extracted with ethyl acetate, and the combined organicextracts were washed with water, then brine (3×), dried (MgSO₄) andevaporated under reduced pressure to give a gum. The crude product waspurified by column chromatography on silica gel using an elutiongradient of ethyl acetate:pentane (0:100 to 100:0) to afford the titlecompound as a brown solid, 3.02 g.

[0503]¹Hnmr (CDCl₃, 400 MHz) δ: 2.00 (m, 1H), 2.15-2.38 (m, 4H), 2.58(m, 4H), 3.69 (m, 2H), 3.85 (m, 2H), 3.95 (d, 1H), 4.45 (t, 1H), 4.62(d, 1H), 7.00 (d, 1H), 7.26 (m, 1H), 7.40 (dd, 2H), 7.61 (m, 2H).

[0504] LRMS: m/z (TSP⁺) 421.0, 423.0 [MH⁺]

Preparation 2a 5-(3,4-Difluorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-1-(6-methyl-2-pyridinyl)-2-piperidinone

[0505]

[0506] The title compound was obtained as a brown foam in 63% yield from5-(3,4-difluorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidinone (EP992493) and 2-bromo-6-methylpyridine, following the procedure describedin preparation 2.

[0507]¹Hnmr (CDCl₃, 400 MHz) δ: 1.98 (m, 1H), 2.15-2.38 (m, 4H), 2.60(m, 4H), 3.69 (m, 2H), 3.85 (m, 2H), 3.95 (d, 1H), 4.45 (t, 1H), 4.62(d, 1H), 7.00 (d, 1H), 7.18 (m, 2H), 7.38 (m, 2H), 7.61 (t, 1H).

[0508] LRMS: m/z (TSP⁺) 389.1 [MH⁺]

Preparations 3 to 6

[0509] The following compounds of the general formula:

[0510] were prepared from (5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-yl methyl)-2-piperidinone (WO 9807722) and the appropriatebromide, according to the procedure described in preparation 2. Prep.Yield No. R (%) Data 3

17 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.90-2.35 (m, 9H), 3.62 (m, 2.5H), 3.80 (m,2H), 4.04 (d, 0.5H), 4.22 (d, 0.5H), 4.36 (t, 1H), 4.50 (d, 0.5H), 7.18(m, 1.5H), 7.40 (m, 1.5H), 7.55 (m, 1.5H), 7.80 (s, 0.5H), 8.36 (d, 1H).LRMS: m/z (TSP⁺) 421.4, 423.3 [MH⁺] 4

28 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.92 (m, 1H), 2.18-2.38 (m, 7H), 2.56 (m,1H), 3.64 (m, 2H), 3.84 (m, 2H), 3.92 (dd, 1H), 4.40 (m, 1H), 4.58 (m,1H), 7.12 (m, 2H), 7.36 (dd, 1H), 7.44 (m, 2H), 8.28 (s, 1H). LRMS : m/z(TSP⁺) 421.1, 423.4 [MH⁺] 5

19 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.94 (dd, 1H), 2.22 (m, 4H), 2.36 (s, 3H),2.58 (m, 1H), 3.62 (m, 2H), 3.84 (m, 2H), 3.94 (d, 1H), 4.40 (t, 1H),4.60 (d, 1H), 6.95 (d, 1H), 7.22 (dd, 1H), 7.40 (d, 2H), 7.48 (s, 1H),8.35 (d, 1H). LRMS: m/z (TSP⁺) 421.1, 422.7 [MH⁺] 6

16 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.32 (t, 3H), 1.93 (dd, 1H), 2.20 (m, 4H),2.56 (m, 1H), 2.80 (q, 2H), 3.68 (m, 2H), 3.82 (m, 3H), 4.41 (t, 1H),4.80 (d, 1H), 6.96 (d, 1H), 7.30 (d, 1H), 7.38 (m, 2H), 7.58 (dd, 1H),7.62 (d, 1H). LRMS: m/z (TSP⁺) 435.2, 437.2 [MH⁺]

Preparation 7 2-Bromo-6-methoxypyridine

[0511]

[0512] Dried sodium (970 mg, 42.2 mmol) was added portionwise to cooledmethanol (50 ml) under nitrogen, and once addition was complete,2,6-dibromopyridine (10 g, 42.2 mmol) was added portionwise. Theresulting suspension was heated under reflux for 24 hours. The cooledreaction was concentrated under reduced pressure, the residue dilutedwith water (100 ml), and extracted with ethyl acetate (2×75 ml). Theorganic extracts were dried (MgSO₄), and evaporated under reducedpressure to give a pale yellow oil. The crude product was purified bycolumn chromatography on silica gel using an elution gradient ofpentane:ethyl acetate (100:0 to 98:2) to give the title compound as aclear oil, 4.23 g.

[0513]¹Hnmr (CDCl₃, 400 MHz) δ: 3.93 (s, 3H), 6.67 (d, 1H), 7.05 (d,1H), 7.40 (dd, 1H).

Preparation 8(5S)-5-(3,4-Dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-1-(6-methoxy-2-pyridinyl)-2-piperidinone

[0514]

[0515] A mixture of (5S)-5-(3,4-d ichlorophenyl)-5-(1,3-d ioxolan-2-ylmethyl)-2-piperidinone (WO 9807722) (4.7 g, 14.3 mmol), potassiumcarbonate (2.97 g, 21.4 mmol), copper (I) iodide (3.0 g, 15.7 mmol) andthe bromide from preparation 7 (4.03 g, 21.4 mmol) in1-methyl-2-pyrrolidinone (25 ml) was stirred at 140° C. for 4 hours,followed by 18 hours at room temperature. The cooled mixture was pouredinto 2N hydrochloric acid (100 ml), then treated with 0.88 ammonia (100ml). This aqueous mixture was extracted with ethyl acetate (2×200 ml),the combined organic extracts were washed with water (50 ml), then brine(100 ml), dried (MgSO₄) and evaporated under reduced pressure to give anoil. The crude product was purified by column chromatography on silicagel using an elution gradient of dichloromethane:methanol (100:0 to98:2). The resulting product was dissolved in ether (100 ml), thesolution washed with water (5×20 ml), dried (MgSO₄) and evaporated underreduced pressure to afford the title compound as a foam, 2.85 g.

[0516]¹Hnmr (CDCl₃, 400 MHz) δ: 1.95 (dd, 1H), 2.18-2.32 (m, 4H), 2.59(m, 1H), 3.70 (q, 2H), 3.81 (d, 1H), 3.87 (q, 2H), 3.99 (s, 3H), 4.42(m, 1H), 4.88 (dd, 1H), 6.60 (d, 1H), 7.27 (d, 1H), 7.33 (dd, 1H), 7.41(d, 1H), 7.61 (dd, 1H), 7.65 (d, 1H).

[0517] LRMS: m/z (TSP⁺) 437.1, 439.1 [MH⁺]

Preparation 9(5S)-5-(3,4-Dichlorophenyl)-5-(2,2-dimethoxyethyl)-1-(2-pyridinyl)-2-piperidinone

[0518]

[0519] Amberlyst® 15 ion-exchange resin (260 g) was carefully added to asolution of the acetal from preparation 1 (129 g, 0.317 mol) in methanol(800 ml), and the mixture stirred at room temperature for 18 hours. Themixture was filtered, and the resin washed with a methanol:0.88 ammoniasolution (10:1, 4×500 ml), and methanol (2×500 ml). The combinedfiltrate and washings were evaporated under reduced pressure to give abrown solid. The solid was partitioned between dichloromethane (600 ml)and water (300 ml), the layers separated, and the aqueous phaseextracted with further dichloromethane (2×100 ml). The combined organicextracts were washed with brine, dried (MgSO₄) and evaporated underreduced pressure to give a pale yellow oil. This oil was triturated withether, and the resulting precipitate was filtered and dried to affordthe title compound as a solid, 72 g.

[0520]¹Hnmr (CDCl₃, 400 MHz) δ: 2.04 (t, 2H), 2.15-2.40 (m, 3H), 2.60(m, 1H), 3.17 (d, 6H), 3.92 (d, 1H), 4.01 (t, 1H), 4.68 (d, 1H), 7.15(t, 1H), 7.24 (d, 1H), 7.43 (d, 1H), 7.52 (s, 1H), 7.68 (m, 2H), 8.52(d, 1H).

[0521] LRMS: m/z (ES⁺) 409.0, 411.0 [MH⁺]

Preparation 10(5S)-5-(3,4-Dichlorophenyl)-5-(2,2-dimethoxyethyl)-1-(6-methoxy-2-pyridinyl)-2-piperidinone

[0522]

[0523] The title compound was obtained as a golden oil (86%) from theacetal of preparation 8, following a similar procedure to that describedin preparation 9.

[0524]¹Hnmr (CDCl₃, 400 MHz) δ: 1.95-2.30 (m, 5H), 2.58 (m, 1H), 3.17(s, 3H), 3.19 (s, 3H), 3.72 (d, 1H), 3.92 (m, 1H), 4.00 (s, 3H), 4.90(dd, 1H), 6.61 (d, 1H), 7.25 (d, 1H), 7.30 (dd, 1H), 7.42 (d, 1H), 7.61(dd, 1H), 7.68 (s, 1H).

Preparation 11a[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]acetaldehyde

[0525]

[0526] A solution of the acetal from preparation 9 (72 g, 0.176 mol) intetrahydrofuran (250 ml) was added to an ice-cooled solution ofhydrochloric acid (2N, 880 ml), and the solution stirred at roomtemperature for 18 hours. The mixture was re-cooled in ice, neutralisedby the addition of sodium bicarbonate, then basified to pH 9 using 2Nsodium hydroxide solution. This aqueous solution was extracted withethyl acetate (2×1.5L), the combined extracts washed with 2N sodiumhydroxide (5×300 ml), dried (MgSO₄) and evaporated under reducedpressure to afford the title compound as a pale yellow gum, 47 g.

[0527]¹Hnmr (CDCl₃, 300 MHz) δ: 2.20-2.46 (d, 3H), 2.63 (m, 1H), 2.79(d, 1H), 2.95 (d, 1H), 4.09 (d, 1H), 4.70 (d, 1H), 7.16 (m, 1H), 7.30(m, 1H), 7.44 (d, 1H), 7.56 (s, 1H), 7.72 (m, 2H), 8.48 (d, 1H), 9.55(s, 1H).

Preparation 11b[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]acetaldehydeHydrochloride

[0528] Amberlyst® 15 resin (13 g) was added to a solution of the acetalfrom preparation 1 (1.34 g, 3.4 mmol) in methanol (50 ml), and thereaction stirred at room temperature for 18 hours. The mixture wasfiltered, the resin washed with a solution ofdichloromethane:methanol:0.88 ammonia (90:10:1), and the combinedfiltrate evaporated under reduced pressure. The residue was partitionedbetween diethyl ether and sodium hydroxide solution, the layersseparated, and the ether extract was washed with brine, dried (MgSO₄)and evaporated under reduced pressure. The residue was dissolved inhydrochloric acid (3N), and the solution stirred at room temperature for2 hours. The solution was carefully basified using 2N sodium hydroxidesolution, and extracted with diethyl ether (3×). The combined organicextracts were dried (MgSO₄) and concentrated under reduced pressure. Theproduct was treated with ethereal hydrochloric acid, then evaporatedunder reduced pressure, to afford the title compound as a white foam,460 mg.

[0529]¹Hnmr (CDCl₃, 300 MHz) δ: 2.42 (t, 2H), 2.55 (m, 1H), 2.75 (m,1H), 3.10 (m, 3H), 4.55 (d, 1H), 4.70 (d, 1H), 7.34 (m, 1H), 7.46 (m,2H), 7.58 (dd, 1H), 7.90 (d, 1H), 8.20 (dd, 1H), 8.64 (d, 1H), 9.58 (s,1H).

Preparation 12a[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(6-methyl-2-pyridinyl)piperidinyl]acetaldehyde

[0530]

[0531] 5N Hydrochloric acid (40 ml) was added dropwise to an ice-cooledsolution of the acetal from preparation 2 (3.8 g, 9 mmol) intetrahydrofuran (40 ml), and the reaction stirred at room temperaturefor 24 hours. The mixture was evaporated, and the residue neutralised bythe addition of aqueous sodium bicarbonate solution. The aqueoussolution was extracted with ethyl acetate (2×), the combined organicextracts dried (MgSO₄), and evaporated under reduced pressure to givethe title compound, 2.05 g.

[0532]¹Hnmr (CDCl₃, 300 MHz) δ: 2.24 (m, 1H), 2.38 (m, 2H), 2.56 (s,3H), 2.58 (m, 1H), 2.88 (dd, 1H), 2.96 (dd, 1H), 4.05 (d, 1H), 4.66 (d,1H), 7.00 (d, 1H), 7.30 (d, 1H), 7.42 (d, 1H), 7.44 (d, 1H), 7.60 (dd,1H), 7.65 (d, 1H), 9.56 (s, 1H).

Preparation 12b[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(6-methyl-2-pyridinyl)piperidinyl]acetaldehydeHydrochloride

[0533] Amberlyst® 15 resin (320 g) was added to an ice-cooled solutionof the acetal from preparation 2 (156 g, 352 mmol) in methanol (1L), andthe reaction then stirred at room temperature for 20 hours. The mixturewas filtered through Arbocel®, and the resin washed with a (80:20)methanolic ammonia solution (4×1 L) and then dichloromethane (2×1 L),filtering between each wash. The combined filtrates were concentratedunder reduced pressure and the residue partitioned between water (1L)and ethyl acetate (2L), and the layers separated. The organic phase waswashed with water (2×500 ml), and the combined aqueous solutionsextracted with ethyl acetate (500 ml). This organic extract was washedwith brine, dried (MgSO₄) and evaporated under reduced pressure to givea brown oil, 136 g.

[0534]¹Hnmr (CDCl₃, 300 MHz) δ: 2.02 (m, 2H), 2.15-2.39 (m, 3H), 2.59(m, 4H), 3.18 (s, 3H), 3.22 (s, 3H), 3.83 (d, 1H), 4.00 (m, 1H), 4.78(dd, 1H), 7.00 (dd, 1H), 7.30 (dd, 1H), 7.42 (m, 2H), 7.60 (dd, 1H),7.65 (d, 1H).

[0535] A solution of the oil in tetrahydrofuran (280 ml) was added to anice-cooled solution of 3N hydrochloric acid (530 ml), and the solutionstirred at room temperature for 3 hours. The solution was diluted withethyl acetate (500 ml), and neutralised using sodium bicarbonate. 2NSodium hydroxide was added to give pH 9, the phases separated, and theorganic layer washed with 2N sodium hydroxide (3×100 ml). The combinedaqueous washes were extracted with ethyl acetate, then the combinedorganic solutions washed with brine, dried (MgSO₄) and evaporated underreduced pressure. The residual oil was purified by column chromatographyon silica gel using ethyl acetate as eluant to give a yellow oil, 94 g.This was dissolved in dichloromethane, and treated with an excess ofethereal hydrochloric acid, and the solution evaporated under reducedpressure. The residue was azeotroped with dichloromethane, to give thetitle compound as a yellow foam.

[0536]¹Hnmr (CDCl₃, 400 MHz) δ: 2.27-2.52 (m, 3H), 2.66 (m, 1H), 2.94(s, 3H), 3.17 (s, 2H), 4.38 (d, 1H), 4.68 (d, 1H), 7.22 (d, 1H), 7.44(m, 4H), 8.15 (dd, 1H), 9.52 (s, 1H).

Preparation 12c[3-(3,4-difluorophenyl)-6-oxo-1-(6-methyl-2-Pyridinyl)piperidinyl]acetaldehyde

[0537]

[0538] 6N Hydrochloric acid (16 ml) was added dropwise to an ice-cooledsolution of the acetal from preparation 2a (3.42 g, 9 mmol) in methanol(40 ml), and the reaction stirred at room temperature for 24 hours. Themixture was evaporated, and the residue neutralised by the addition ofaqueous sodium bicarbonate solution. The aqueous solution was extractedwith ethyl acetate (2×), the combined organic extracts washed withbrine, dried (MgSO₄) and evaporated under reduced pressure to give ayellow oil, 3.5 g. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(98:2:0.2) as eluant to give the title compound as a yellow gum, (750mg).

[0539]¹Hnmr (CDCl₃, 300 MHz) δ: 2.21-2.42 (m, 3H), 2.48-2.64 (m, 4H),2.78 (dd, 1H), 2.96 (dd, 1H), 4.05 (d, 1H), 4.66 (d, 1H), 7.00 (d, 1H),7.18 (m, 2H), 7.36 (m, 1H), 7.46 (d, 1H), 7.60 (m, 1H), 9.55 (s, 1H).

[0540] LRMS: m/z (TSP⁺) 345.1 [MH⁺].

Preparations 13 to 16

[0541] The following compounds of the general formula:

[0542] were prepared from the corresponding acetals following theprocedure described in preparation 12a. Prep. Yield No. R (%) Data 13

69 LRMS: m/z (TSP⁺) 377.2, 378.7 [MH⁺] 14

78 LRMS: m/z (TSP⁺) 377.5, 379.5 [MH⁺] 15

56 ¹Hnmr (CDCl₃, 400 MHz) δ: 2.00-2.46 (m, 6H), 2.58 (m, 1H), 2.80 (m,1H), 3.02 (m, 1H), 4.05 (m, 1H), 4.30 (d, 0.5H), 4.60 (d, 0.5H), 7.20(m, 1H), 7.41-7.83 (m, 4H), 8.39 (m, 1H), 9.55 (s, 1H). LRMS: m/z (TSP⁺)377.2, 378.2 [MH⁺] 16

90 ¹Hnmr (CDCl₃, 400 MHz) δ: 1.30 (t, 3H), 2.20-2.40 (m, 2H), 2.38 (m,2H), 2.60 (m, 1H), 2.80 (q, 2H), 2.92 (d, 1H), 4.00 (d, 1H), 4.76 (d,1H), 6.96 (d, 1H), 7.32 (dd, 1H), 7.40 (d, 1H), 7.44 (d, 1H), 7.60 (dd,1H), 7.74 (d, 1H), 9.54 (s, 1H). LRMS: m/z (TSP⁺) 391.0, 393.2 [MH⁺]

Preparation 17{(3S)-3-(3,4-Dichlorophenyl)-1-[6-(dimethylamino)-2-pyridinyl]-6-oxopiperidinyl}acetaldehydeHydrochloride

[0543]

[0544] Copper (I) iodide (6.4 g, 33.3 mmol), potassium carbonate (6.3 g,45.4 mmol) and 6-bromo-2-(dimethylamino)pyridine (WO 9843971) (9 g, 45.4mmol) were added consecutively to a solution of(5S)-5-(3,4-dichlorophenyl)-5-(1,3-dioxolan-2-ylmethyl)-2-piperidinone(WO 9807722) (10 g, 30.3 mmol), in 1-methyl-2-pyrrolidinone (50 ml), andthe mixture was stirred at 140° C. for 4 hours. The cooled mixture waspoured into 4N hydrochloric acid, then carefully basified using 10%aqueous ammonia. The aqueous mixture was extracted with ethyl acetate(3×200 ml), and the combined organic extracts were washed with brine,dried (MgSO₄) and evaporated under reduced pressure to give an orangeoil. The crude product was purified by column chromatography on silicagel using methanol:dichloromethane (5:95) as eluant, and repeated usingethyl acetate as eluant. The product was treated with 1N etherealhydrochloric acid, and evaporated under reduced pressure to afford thetitle compound.

[0545]¹Hnmr (CDCl₃, 400 MHz) δ: 2.21-2.43 (m, 2H), 2.55-2.81 (m, 2H),3.05 (d, 1H), 3.18 (d, 1H), 3.38 (s, 6H), 4.39 (q, 2H), 6.90 (d, 1H),6.95 (d, 1H), 7.25 (d, 1H), 7.42 (d, 1H), 7.48 (s, 1H), 7.86 (dd, 1H),9.53 (s, 1H).

[0546] LRMS: m/z (TSP⁺) 406.1, 408.1 [MH⁺]

Preparation 18{(3S)-3-(3,4-Dichlorophenyl)-1-[6-methoxy-2-pyridinyl]-6-oxopiperidinyl}acetaldehydeHydrochloride

[0547]

[0548] A solution of the acetal from preparation 10 (2.47 g, 5.62 mmol)in tetrahydrofuran (10 ml) was added dropwise to cooled (5° C.)hydrochloric acid (14 ml, 2N, 28 mmol), and the reaction stirred at roomtemperature for 18 hours. Tlc analysis showed starting materialremaining, so additional hydrochloric acid (10 ml, 2N), andtetrahydrofuran (10 ml) were added and the reaction stirred for afurther 24 hours at room temperature. The solution was cooled in ice,neutralised by the addition of sodium bicarbonate, and basified by theaddition of 1N sodium hydroxide solution (10 ml). The mixture wasextracted with ethyl acetate (3×50 ml), and the combined organicextracts washed with brine (2×20 ml), dried (MgSO₄) and concentratedunder reduced pressure. The crude product was purified by columnchromatography on silica gel using ethyl acetate:pentane (75:25) aseluant, to afford the title compound as a foam, 760 mg.

[0549]¹Hnmr (CDCl₃, 400 MHz) δ: 2.24-2.40 (m, 3H), 2.60 (m, 1H),2.70-3.00 (ABq, 2H), 3.95 (d, 1H), 3.98 (s, 3H), 4.81 (d, 1H), 6.62 (d,1H), 7.27 (d, 1H), 7.35 (dd, 1H), 7.45 (d, 1H), 7.63 (dd, 1H), 7.69 (d,1H), 9.52 (s, 1H).

Preparation 19 2-(3-Fluorophenoxy)ethylamine Hydrochloride

[0550]

[0551] A solution of 3-fluorophenol (20 g, 178 mmol) in tetrahydrofuran(100 ml) and N,N-dimethylformamide (100 ml), was added dropwise to acooled (10° C.) suspension of sodium hydride (13.38 g, 80% dispersion inmineral oil, 446 mmol) in tetrahydrofuran (200 ml). Once addition wascomplete, the mixture was stirred at room temperature for 45 minutes.2-Bromoethylamine hydrobromide (36.56 g, 178 mmol) was added portionwiseover 30 minutes, and then the reaction stirred at 45° C. for 18 hours.Water (800 ml) was carefully added to the cooled solution, and themixture extracted with ethyl acetate (3×250 ml). The organic solutionswere extracted with 2M hydrochloric acid (3×200 ml), and these acidicfractions then basified to pH 10 using 2N sodium hydroxide solution.This was re-extracted with ethyl acetate (4×250 ml), these combinedorganic solutions dried (MgSO₄) and evaporated under reduced pressure.The residual oil was dissolved in ethyl acetate (200 ml), and thesolution treated with 1N ethereal hydrochloric acid (150 ml), and thesuspension stirred for 2 hours. The resulting precipitate was filteredand dried in vacuo, to afford the title compound as a white solid, 8.0g.

[0552]¹Hnmr (CD₃OD, 400 MHz) δ: 3.35 (s, 2H), 4.20 (s, 2H), 6.65-6.82(m, 3H), 7.25 (m, 1H).

[0553] LRMS: m/z (ES⁺) 156 [MH⁺]

Preparation 20 1-Methyl-2-oxo-1,2-dihydro-4-pyridinecarbonitrile

[0554]

[0555] Oxalyl chloride (250 μl, 2.87 mmol) was added to an ice-cooledsolution of N,N-dimethylformamide (243 μl, 3.14 mmol) in acetonitrile (3ml). A suspension of 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarboxamide(J.O.C. 24; 1959; 196) (201.5 mg, 1.32 mmol) and pyridine (470 μl, 5.82mmol) in acetonitrile (20 ml) was added to the resulting whitesuspension, and the mixture stirred at room temperature for 18 hours.The mixture was diluted with water (20 ml), and extracted with ethylacetate (2×100 ml). The combined organic solutions were washed withbrine, dried (MgSO₄) and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel using ethylacetate:pentane (75:25), then dichloromethane:methanol (90:10) aseluants, to afford the title compound as a pale yellow solid, 112.3 mg.

[0556]¹Hnmr (CDCl₃, 300 MHz) δ: 3.40 (s, 3H), 6.27 (d, 1H), 6.93 (s,1H), 7.41 (d, 1H).

Preparation 21 4-(Aminomethyl)-1-methyl-2(1H)-pyridinone

[0557]

[0558] Raney Nickel® (10 mg) was added to a solution of the nitrile frompreparation 20 (112.3 mg, 0.84 mmol) and potassium hydroxide (69.7 mg,1.24 mmol) in ethanol (15 ml) and the mixture hydrogenated at 60 psi for18 hours. The mixture was filtered through Arbocel®, and washed throughwith ethanol. The filtrate was evaporated under reduced pressure, andthe residue partitioned between water and dichloromethane, and thephases separated. The aqueous layer was evaporated under reducedpressure and the residue triturated with methanol (70 ml). This organicsolution was concentrated under reduced pressure and the residuepurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (90:10:1) as eluant to give thetitle compound as a crystalline solid, 66.3 mg.

[0559]¹Hnmr (CDCl₃, 300 MHz) δ: 3.50 (s, 3H), 3.69 (s, 2H), 6.11 (d,1H), 6.49 (s, 1H), 7.21 (d, 1H).

[0560] LRMS: m/z 277.3 [2MH⁺]

Preparation 22 1-Acetyl-4-piperidinamine

[0561]

[0562] 0.88 Ammonia (85 ml) was added to a solution ofN-acetylpiperidone (15 g, 106 mmol) in methanol (120 ml), followed bypalladium hydroxide (2 g) and the mixture hydrogenated at roomtemperature and 60 psi for 18 hours. The reaction mixture was filteredthrough Arbocel®, the filtrate concentrated under reduced pressure andthe residue azeotroped with toluene to give a yellow oil. The crudeproduct was purified by column chromatography on silica gel using anelution gradient of dichloromethane:methanol:0.88 ammonia (96:3.5:0.5 to84:14:2) to afford the title compound as a clear oil, 9.6 g.

[0563]¹Hnmr (CDCl₃, 400 MHz) δ: 1.20 (m, 2H), 1.80 (m, 2H), 2.04 (s,3H), 2.66 (m, 1H), 2.88 (m, 1H), 3.03 (m, 1H), 3.75 (m, 1H), 4.42 (m,1H).

[0564] LRMS: m/z (ES⁺) 165 [MNa⁺]

Preparation 23 tert-Butyl 3-[(acetylamino)methyl]-1-azetidinecarboxylate

[0565]

[0566] Triethylamine (0.76 ml, 5.45 mmol) and acetic anhydride (0.43 ml,4.56 mmol) were added to an ice-cooled solution of tert-butyl3-(aminomethyl)-1-azetidinecarboxylate (J. Med. Chem. 2001; 44(1); 94)(850 mg, 4.56 mmol) in dichloromethane (50 ml), and the reaction stirredfor 30 minutes. The solution was washed with water (50 ml), brine (50ml), dried (MgSO₄) and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel using ethylacetate as eluant to afford the title compound as a yellow oil.

[0567]¹Hnmr (CDCl₃, 300 MHz) δ:1.43 (s, 9H), 2.00 (s, 3H), 2.72 (m, 1H),3.44 (m, 2H), 3.61 (m, 2H), 4.00 (m, 2H), 5.74 (bs, 1H).

[0568] LRMS: m/z (ES⁻) 227 (M−H)⁻

Preparation 24 tert-Butyl3-{[acetyl(methyl)amino]methyl}-1-azetidinecarboxylate

[0569]

[0570] Sodium hydride (154.7 mg, 60% dispersion in mineral oil, 3.87mmol) was added to a solution of the acetamide from preparation 23 (740mg, 3.24 mmol) in tetrahydrofuran (20 ml), and the mixture stirred for45 minutes. Methyl iodide (0.40 ml, 6.42 mmol) was added and thereaction stirred at room temperature for 18 hours. Water (10 ml) wasthen carefully added, and the tetrahydrofuran removed under reducedpressure. The aqueous solution was extracted with dichloromethane (2×30ml), the combined organic solutions washed with brine, dried (MgSO₄) andevaporated under reduced pressure to give the title compound as a yellowoil.

[0571]¹Hnmr (CDCl₃, 300 MHz) 6 (mixture of rotamers in 8:3 ratio): 1.43(s, 9H), 2.08, 2.16 (s, 3H), 2.81 (m, 1H), 2.90, 3.02 (s, 3H), 3.50-3.75(m, 4H), 3.96-4.10 (m, 2H).

[0572] LRMS: m/z (ES⁺) 243.2 [MH⁺]

Preparation 25 N-(3-Azetidinyl methyl)-N-methylacetamide

[0573]

[0574] Trifluoroacetic acid (3 ml) was added to an ice-cooled solutionof the protected amine from preparation 24 (720 mg, 2.97 mmol) indichloromethane (20 ml), and the reaction stirred for 3 hours. Thesolution was diluted with toluene (30 ml), then concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel using an elution gradient of dichloromethane:methanol:0.88ammonia (90:10:1 to 80:20:3), and the product triturated with a solutionof ether:ethyl acetate (50:50, 3×30 ml), to give the title compound as afoam.

[0575]¹Hnmr (CD₃OD, 300 MHz) δ: 2.10 (s, 3H), 3.08 (s, 3H), 3.21 (m,1H), 3.64 (d, 2H), 3.95 (m, 2H), 4.09 (m, 2H).

[0576] LRMS: m/z (TSP⁺) 285.3 [MH⁺]

Preparation 26 4-Methyl-4piperidinol

[0577]

[0578] A mixture of 1-benzyl-4-methyl-4-piperidinol (Tet.Lett. 37;8;1996; 1297) (1.58 g, 7.7 mmol) and palladium hydroxide (500 mg) inethanol (50 ml) was hydrogenated at 50 psi and 50° C. for 18 hours. Thecooled mixture was filtered through Arbocel®, and the filtrateevaporated under reduced pressure to give the title compound as a solid,880 mg.

[0579]¹Hnmr (CDCl₃, 400 MHz) δ: 1.22 (s, 3H), 1.58 (m, 4H), 2.82 (m,2H), 2.98 (m, 2H).

Preparation 27 tert-Butyl3-(4-hydroxy-4-methyl-1-piperidinyl)-1-azetidinecarboxylate

[0580]

[0581] A mixture of the piperidine from preparation 26 (220 mg, 1.91mmol), tert-butyl 3-iodo-1-azetidinecarboxylate (600 mg, 2.0 mmol) (EP992493) and potassium carbonate (276 mg, 2.0 mmol) in1-methyl-2-pyrrolidinone (10 ml) was stirred at 80° C. for 48 hours. Themixture was partitioned between water and ethyl acetate, and the layersseparated. The organic phase was washed with water, then brine, dried(Na₂SO₄), and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:0.5)to afford the title compound, 162 mg.

[0582]¹Hnmr (CDCl₃, 400 MHz) δ: 1.20 (s, 3H), 1.38 (s, 9H), 1.60 (m,5H), 2.20 (t, 2H), 2.42 (m, 2H), 3.05 (m, 1H), 3.88 (m, 2H), 3.90 (t,2H).

[0583] LRMS: m/z (TSP⁺) 271.1 [MH⁺]

Preparation 28 1-(3-Azetidinyl)-4-methyl-4-piperidinol Trifluoroacetate

[0584]

[0585] A mixture of the protected azetidine from preparation 27 (160 mg,0.6 mmol) in trifluoroacetic acid (1 ml) and dichloromethane (1 ml), wasstirred at room temperature for 2 hours. The solution was concentratedunder reduced pressure and azeotroped with toluene, to afford the titlecompound as a yellow gum, 155 mg.

[0586]¹Hnmr (CDCl₃, 400 MHz) δ: 1.25 (s, 3H), 1.76 (d, 2H), 1.90 (m,2H), 3.16 (t, 2H), 3.25 (m, 3H), 4.35 (m, 4H), 4.50 (m, 2H).

[0587] LRMS: m/z (ES⁺) 172 [MH⁺]

Preparation 29 1-Benzhydryl-3-(2-methoxyphenyl)-3-azetidinol

[0588]

[0589] 2-Methoxyphenylmagnesium bromide (5.9 ml, 1M solution intetrahydrofuran, 5.9 mmol) was added to a cooled (−78° C.) solution of1-benzhydryl-azetidin-3-one (WO 9412181) (1 g, 4.2 mmol) intetrahydrofuran (20 ml), and the reaction stirred at −78° C. for 15minutes, then allowed to warm to room temperature over 30 minutes. Themixture was partitioned between water (100 ml) and ethyl acetate (100ml), the layers separated, and the aqueus phase extracted with ethylacetate (100 ml). The combined organic solutions were washed with brine(100 ml), dried (MgSO₄) and evaporated under reduced pressure. Theresidual yellow oil was purified by column chromatography on silica gelusing pentane:ethyl acetate (50:50) as eluant to afford the titlecompound as a white foam.

[0590]¹Hnmr (CDCl₃, 400 MHz) δ: 3.58 (m, 4H), 3.95 (s, 3H), 4.42 (s,1H), 6.94 (d, 1H), 7.00 (dd, 1H), 7.20 (m, 2H), 7.28 (m, 6H), 7.46 (m,4H).

[0591] LRMS: m/z (TSP⁺) 346.1 [MH⁺]

Preparation 30 3-(2-Methoxyphenyl)-3-azetidinol Hydrochloride

[0592]

[0593] A mixture of palladium hydroxide (1 g, 7.14 mmol), and theazetidine from preparation 29 (950 mg, 2.75 mmol) in methanol (100 ml)was hydrogenated at 50° C. and 50 psi for 18 hours. The cooled reactionmixture was filtered through Arbocel®, and 1N ethereal hydrochloric acidwas added to the filtrate. The filtrate was evaporated under reducedpressure, azeotroped with dichloromethane, and the product trituratedwith diethyl ether, to afford the title compound as a white solid.

[0594]¹Hnmr (CD₃OD, 400 MHz) δ: 3.95 (s, 3H), 4.15 (d, 2H), 4.62 (d,2H), 6.99 (dd, 1H), 7.07 (d, 1H), 7.30 (d, 1H), 7.38 (dd, 1H).

[0595] LRMS: m/z (TSP⁺) 180.1 [MH⁺]

Preparation 31 3-Tetrahydro-2H-pyran-4-yl-azetidine p-toluenesulfinate

[0596]

[0597] Sodium (390 mg, 16.6 mmol) was added to a solution of naphthalene(2.61 g, 20.4 mmol) in 1,2-dimethoxyethane (25 ml), and the solutionstirred at room temperature for 4 hours. This solution was then addeddropwise to a cooled (−70° C.) solution of 4-methylphenyl3-tetrahydro-2H-pyran-4-yl-1-azetidinesulfonate (EP 962457) (1 g, 3.39mmol) in 1,2-dimethoxyethane (25 ml), and once the addition wascomplete, the mixture was stirred at −70° C. for 20 minutes. Thereaction was allowed to warm to room temperature, the reaction quenchedby the addition of water and concentrated under reduced pressure. Theresidual gum was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (80:20:3) as eluant to give thetitle compound as an off-white gum, 690 mg.

[0598]¹Hnmr (CD₃OD, 400 MHz) δ: 1.18 (m, 2H), 1.58 (m, 2H), 1.81 (m,1H), 2.38 (s, 3H), 2.68 (m, 1H), 3.40 (t, 2H), 3.90 (m, 4H), 4.04 (t,2H), 7.22 (d, 2H), 7.55, 7.72 (d, 2H).

Preparation 32 N-(4-Phenyl-4-piperidinyl)acetamide

[0599]

[0600] A mixture of N-(1-Benzyl-4-phenyl-4-piperidinyl)acetamide(Bioorg. Med. Chem. Lett. 1996; 6(19); 2307) (49 g, 158 mmol), andpalladium hydroxide (5 g) in methanol (600 ml) was hydrogenated at 50psi and room temperature for 18 hours. The mixture was filtered, thefiltrate concentrated under reduced pressure and the residue azeotropedwith dichloromethane to give the title compound as a foam.

[0601]¹Hnmr (CDCl₃, 300 MHz) δ: 2.00 (m, 5H), 2.38 (m, 2H), 2.97 (m,4H), 7.19-7.40 (m, 5H).

Preparation 33 N-[1-(1-Benzhydryl-3-azetidinyl)-4-phenyl-4-piperidinyl]acetamide

[0602]

[0603] A mixture of 1-(diphenylmethyl)-3-azetidinylmethanesulfonate (8g, 25.2 mmol), the amine from preparation 32 (7.1 g, 27.7 mmol) andtriethylamine (4.6 ml, 32.8 mmol) in acetonitrile (80 ml) was heatedunder reflux for 18 hours. The cooled mixture was concentrated underreduced pressure, the residue partitioned between sodium bicarbonatesolution and ethyl acetate, and the layers separated. The organic phasewas washed with water, then brine, dried (MgSO₄) and evaporated underreduced pressure. The residual foam was purified by columnchromatography on silica gel using an elution gradient (hexane:ethylacetate:methanol 80:20:0 to 0:100:0 to 0:93:7) to afford the titlecompound as a white solid, 2.31 g.

[0604]¹Hnmr (CDCl₃, 300 MHz) δ: 2.00 (s, 3H), 2.01-2.20 (m, 4H), 2.37(m, 2H), 2.62 (m, 2H), 2.84-3.06 (m, 3H), 3.41 (t, 2H), 4.41 (s, 1H),5.44 (s, 1H), 7.12-7.54 (m, 15H).

Preparation 34 N-[1-(3-Azetidinyl)-4-phenyl-4-piperidinyl]acetamideDihydrochloride

[0605]

[0606] α-Chloroethylchoroformate (630 μl, 8.63 mmol) was added dropwiseto an ice-cooled solution of the azetidine from preparation 33 (2.3 g,5.23 mmol) in dichloromethane (25 ml), and the solution stirred at roomtemperature for 18 hours. The mixture was concentrated under reducedpressure the residue suspended in methanol (37 ml), potassium carbonate(2.2 g, 15.7 mmol) added, and the mixture heated under reflux for anhour. The cooled mixture was filtered, the filtrate acidifed to pH 3using ethereal hydrochloric acid, then re-filtered. The filtrate wasconcentrated under reduced pressure, the residual gum triturated withdiethyl ether, to give the title compound as a pale brown solid, 1.5 g.

[0607]¹Hnmr (DMSOd₆, 300 MHz) δ:1.92 (s, 2H), 2.30 (m, 1H), 2.48 (s,3H), 2.63 (m, 1H), 3.10 (m, 1H), 4.08 (m, 7H), 4.50 (m, 2H), 7.12-7.65(m, 5H), 8.30 (s, 1H), 9.15 (bs, 1H), 10.10 (bs, 1H).

[0608] LRMS: m/z (TSP⁺) 274.3 [MH⁺]

Preparation 35 Ethyl 4-cyanotetrahydro-2H-pyran-4-carboxylate

[0609]

[0610] Ethyl cyanoacetate (22.6 g, 0.2 mol) and bis(2-chloroethyl)ether(14 g, 0.1 mol) were added to a suspension of potassium carbonate (70 g,0.5 mol) in N,N-dimethylformamide (150 ml), and the mixture stirred at100° C. for 72 hours. The cooled mixture was partitioned between waterand diethyl ether (500 ml), the layers separated and the aqueoussolution extracted with diethyl ether (3×200 ml). The combined organicsolutions were washed with 2N hydrochloric acid (3×100 ml), brine (2×100ml), dried (MgSO₄) and evaporated under reduced pressure to give ayellow oil. This crude product was purified by column chromatography onsilica gel using ethyl acetate:cyclohexane (50:50) as eluant, to affordthe title compound, 9.3 g.

[0611]¹Hnmr (CDCl₃, 400 MHz) δ: 1.34 (t, 3H), 2.00 (m, 2H), 2.14 (m,2H), 3.74 (m, 2H), 3.98 (m, 2H), 4.26 (q, 2H).

Preparation 36 [4-({[(4-Methylphenyl)sulfonyl]amino}methyl)tetrahydro-2H-pyran-4-yl]methyl4-methylbenzenesulfonate

[0612]

[0613] A solution of the ester from preparation 35 (9.3 g, 51 mmol) intetrahydrofuran (50 ml) was added dropwise to a suspension of lithiumaluminium hydride (10 g, 263 mmol) in tetrahydrofuran (200 ml), and onceaddition was complete, the mixture was heated under reflux for an hour.The mixture was cooled in ice, and water (15 ml) in tetrahydrofuran (50ml) was added dropwise. Additional tetrahydrofuran (200 ml) was added,the mixture poured into a suspension of MgSO₄ (200 g) in tetrahydrofuran(300 ml), and the resulting slurry filtered. The solids were washed wellwith tetrahydrofuran, and the combined filtrates evaporated underreduced pressure. The residual gum was dissolved in 1,2-dimethoxyethane(200 ml), and triethylamine (20 ml), p-toluenesulfonyl chloride (29 g,153 mmol) and pyridine (21 ml) added, and the reaction heated underreflux for 18 hours. The cooled mixture was partitioned betweendichloromethane (300 ml) and 2N hydrochloric acid (300 ml), the layersseparated, and the aqueous phase extracted with dichloromethane (5×300ml). The combined organic extracts were washed with brine, dried (MgSO₄)and the mixture filtered through a plug of silica gel. The filtrate wasdiscarded, the silica washed well with ethyl acetate, and this filtrateconcentrated under reduced pressure. The residue was triturated withdiethyl ether, to afford the title compound as a beige solid, 6.0 g.

[0614]¹Hnmr (CDCl₃, 300 MHz) δ: 1.43 (m, 1H), 1.55 (m, 3H), 2.46 (2×s,6H), 3.00 (d, 2H), 3.60 (m, 4H), 3.88 (s, 2H), 4.88 (t, 1H), 7.37 (2×d,4H), 7.77 (2×d, 4H).

[0615] LRMS: m/z (ES⁺) 454 [MH⁺]

Preparation 37 2-[(4-Methylphenyl)sulfonyl]-7-oxa-2-azaspiro[3.5]nonane

[0616]

[0617] Potassium tert-butoxide (2.0 g, 18 mmol) was added to asuspension of the compound from preparation 36 (5.5 g, 12 mmol) in1,2-dimethoxyethane (300 ml), and the reaction stirred at 100° C. for 30minutes. The cooled mixture was concentrated under reduced pressure andthe residue partitioned between dichloromethane and 2N sodium hydroxidesolution, and the layers separated. The aqueous phase was extracted withfurther dichloromethane (2×250 ml), and the combined organic solutionswashed with brine, dried (MgSO₄) and evaporated under reduced pressureto give the title compound as a white solid, 3.3 g.

[0618]¹Hnmr (CDCl₃, 300 MHz) δ:1.57 (m, 4H), 2.48 (s, 3H), 3.51 (m, 8H),7.39 (d, 2H), 7.75 (d, 2H).

[0619] LRMS: m/z (ES⁺) 282 [MH⁺]

Preparation 38 7-Oxa-2-azaspiro[3.5]nonane p-toluenesulphinate

[0620]

[0621] Freshly cut sodium (2.3 g, 100 mmol) was added to a solution ofnapthalene (15.4 g, 120 mmol) in 1,2-dimethoxyethane (100 ml), and themixture stirred at room temperature for 3 hours.

[0622] The compound from preparation 37 (6.0 g, 21 mmol) was dissolvedin 1,2-dimethoxyethane (100 m!), and the solution cooled to −70° C. Theprepared solution of sodium napthalenide was then added, the solutionstirred for 10 minutes, and then quenched by the addition of water (5ml). The solution was allowed to warm to room temperature, potassiumcarbonate (200 g) and additional 1,2-dimethoxyethane (500 ml) added, andthe mixture filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (80:20:5) as eluant, and theproduct azeotroped with toluene (5×100 ml) to give a gum. This wastriturated with ether to afford the title compound as a white solid, 4.1g.

[0623]¹Hnmr (CDCl₃, 300 MHz) δ:1.65 (m, 4H), 2.38 (s, 3H), 3.44 (m, 4H),3.52 (s, 4H), 7.22 (d, 2H), 7.56 (d, 2H).

Preparation 39 tert-Butyl (3R)-3-(acetylamino)-1-pyrrolidinecarboxylate

[0624]

[0625] Di-tert-butyl dicarbonate (1.92 g, 8.8 mmol) was added to asolution of N-[(3R)-pyrrolidinyl]acetamide (1 g, 8 mmol) indichloromethane (30 ml), and the solution cooled in ice. Hünig's base(1.5 ml, 8.8 mmol) was added dropwise, and once addition was completethe reaction was stirred for 2 hours. The mixture was washed with sodiumbicarbonate solution (3×), then brine (3×), dried (MgSO₄) and evaporatedunder reduced pressure to give the title compound, 1.75 g.

[0626]¹Hnmr (CDCl₃, 300 MHz) δ: 1.46 (s, 9H), 1.96 (s, 3H), 2.16 (m,2H), 3.18 (m, 1H), 3.40 (m, 2H), 3.60 (m, 1H), 4.42 (m, 1H), 5.70 (bs,1H).

Preparation 40 tert-Butyl (3S)-3-(acetylamino)-1-pyrrolidinecarboxylate

[0627]

[0628] The title compound was obtained as a colourless gum, fromN-[(3S)-pyrrolidinyl]acetamide, following the procedure described inpreparation.

[0629]¹Hnmr (CDCl₃, 300 MHz) δ: 1.46 (s, 9H), 1.96 (s, 3H), 2.10 (m,2H), 3.16 (m, 1H), 3.38 (m, 2H), 3.58 (m, 1H), 4.42 (m, 1H), 5.52 (bs,1H).

Preparation 41 tert-Butyl(3R)-3-[acetyl(methyl)amino]-1-pyrrolidinecarboxylate

[0630]

[0631] A solution of the pyrrolidine from preparation 39 (1.75 g, 7.7mmol) in N,N-dimethylformamide (5 ml), was added dropwise to a mixtureof sodium hydride (470 mg, 11.7 mmol) in N,N-dimethylformamide (10 ml),and the solution stirred for 30 minutes. Iodomethane (0.8 ml, 8.4 mmol)was added, and the reaction stirred at room temperature for 2 hours.Aqueous ammonium chloride solution was added and the mixture extractedwith ethyl acetate. The combined organic solutions were washed withwater, brine, then dried (MgSO₄) and evaporated under reduced pressureto give the title compound as a yellow gum, 725 mg.

[0632]¹Hnmr (CDCl₃, 300 MHz) δ: 1.44 (s, 9H), 1.90-2.16 (m, 5H), 2.95(s, 3H), 3.12 (m, 1H), 3.30 (m, 1H), 3.50 (m, 2H), 4.38, 5.20 (2×m, 1H).

[0633] LRMS: m/z (TSP⁺) 243.2 [MH⁺]

Preparation 42 tert-Butyl(3S)-3-[acetyl(methyl)amino]-1-pyrrolidinecarboxylate

[0634]

[0635] The title compound was obtained as a yellow gum in 44% yield,from the pyrrolidine from preparation 40, following the proceduredescribed in preparation 41.

[0636]¹Hnmr (CDCl₃, 300 MHz) δ: 1.42 (s, 9H), 1.82-2.15 (m, 5H), 2.84(s, 3H), 3.14 (m, 1H), 3.25 (m, 1H), 3.54 (m, 2H), 4.38, 5.18 (2×m, 1H).

[0637] LRMS: m/z (TSP⁺) 243.2 [MH⁺]

Preparation 43 N-Methyl-N-[(3R)-pyrrolidinyl]acetamide Trifluoroacetate

[0638]

[0639] A mixture of the protected pyrrolidine from preparation 41 (720mg, 2.96 mmol) and trifluoroacetic acid (4 ml) in dichloromethane (4 ml)was stirred at room temperature for 1 hour. The mixture was concentratedunder reduced pressure, the residue azeotroped with toluene (3×),dichloromethane (3×) and diethyl ether (3×) to afford the title compoundas a gum.

[0640]¹Hnmr (CD₃OD, 400 MHz) δ: 2.10 (s, 3H), 2.16 (m, 1H), 2.38 (m,1H), 3.06 (s, 3H), 3.20 (m, 1H), 3.40 (m, 2H), 3.60 (m, 1H), 4.50 (m,1H).

[0641] LRMS: m/z (TSP⁺) 285.2 [MH⁺]

Preparation 44 N-Methyl-N-[(3S)-pyrrolidinyl]acetamide Trifluoroacetate

[0642]

[0643] The title compound was obtained as a gum, from the protectedpyrrolidine from preparation 42, following the procedure described inpreparation 43.

[0644]¹Hnmr (CD₃OD, 400 MHz) δ: 2.08 (s, 3H), 2.18 (m, 1H), 2.38 (m,1H), 3.06 (s, 3H), 3.20 (m, 1H), 3.40 (m, 2H), 3.60 (m, 1H), 4.50 (m,1H).

[0645] LRMS: m/z (TSP⁺) 285.2 [MH⁺]

Preparation 45 tert-Butyl (3R)-3-methoxy-1-pyrrolidinecarboxylate

[0646]

[0647] Sodium hydride (2.2 g, 80% dispersion in mineral oil, 73.2 mmol)was added to an ice-cooled solution of(3R)-N-tert-butoxycarbonylpyrrolidin-3-ol (J. Med. Chem. 41; 25; 1998;4983) (12.5 g, 66.7 mmol) in tetrahydrofuran (330 ml), and the solutionstirred at room temperature for an hour. Methyl iodide (14.5 g, 100mmol) was then added and the reaction stiired for 18 hours. Water (100ml) was added and the mixture concentrated under reduced pressure toremove the organic solvents. The aqueous was extracted with ethylacetate, the combined organic solutions dried (MgSO₄) and evaporatedunder reduced pressure to give the title compound as an oil, 12.48 g.

[0648]¹Hnmr (CDCl₃, 400 MHz) δ: 1.42 (s, 9H), 1.86-2.01 (m, 2H), 3.32(s, 3H), 3.40 (m, 4H), 3.93 (m, 1H).

[0649] Microanalysis found: C, 59.71; H, 9.63; N, 6.71. C₁₀H₁₉NO₃requires C, 59.68; H, 9.52; N, 6.96%.

Preparation 46 tert-Butyl (3S)-3-methoxy-1-pyrrolidinecarboxylate

[0650]

[0651] The title compound was prepared from(3S)-N-tert-butoxycarbonylpyrrolidin-3-ol (U.S. Pat. No. 6,180,627),following the procedure described in preparation 45.

[0652]¹Hnmr (CDCl₃, 400 MHz) δ: 1.42 (s, 9H), 1.84-2.00 (m, 2H), 3.32(s, 3H), 3.40 (m, 4H), 3.92 (m, 1H).

[0653] Microanalysis found: C, 59.72; H, 9.62; N, 6.63. C₁₀H₁₉NO₃requires C, 59.68; H, 9.52; N, 6.96%.

Preparation 47 (3R)-3-Methoxypyrrolidine Trifluoroacetate

[0654]

[0655] Hydrogen chloride was bubbled through a solution of the protectedamine from preparation 45 (24.8 g, 123 mmol) in diethyl ether (615 ml),until saturated, and the solution then stirred for 1 hour at roomtemperature. The reaction was concentrated under reduced pressure, theresidue resuspended in diethyl ether, the solution stirred for 2 hoursthe ether decanted off, and the residue evaporated under reducedpressure. The product was dissolved in ethanol, trifluoroacetic acid(200 ml) added, and the solution evaporated under reduced pressure toafford the title compound.

[0656]¹Hnmr (CDCl₃, 400 MHz) δ: 2.00 (m, 1H), 2.18 (m, 1H), 3.24-3.50(m, 7H), 4.05 (m, 1H), 8.80 (bs, 1H), 9.37 (bs, 1H).

[0657] Microanalysis found: C, 33.76; H, 5.35; N, 5.54.C₅H₁₁NO.1.25CF₃CO₂H;1.25H₂O requires C, 33.84; H, 5.59; N, 5.26%.

Preparation 48 (3S)-3-Methoxypyrrolidine Trifluoroacetate

[0658]

[0659] The title compound was obtained, from the protected amine frompreparation 46, following the procedure described in preparation 47.

[0660]¹Hnmr (CDCl₃, 400 MHz) δ: 2.00 (m, 1H), 2.18 (m, 1H), 3.25-3.48(m, 7H), 4.06 (m, 1H), 8.75 (bs, 1H), 9.24 (bs, 1H).

Preparation 49 N-[(3S)-1-Benzyl pyrrolidinyl]-4-chlorobutanamide

[0661]

[0662] 4-Chlorobutyryl chloride (0.31 ml, 3.1 mmol) was added to amixture of (3S)-1-benzyl-3-pyrrolidinamine (500 mg, 2.8 mmol) intetrahydrofuran (30 ml), and the reaction was stirred at roomtemperature for 2 hours. The mixture was washed with water, then brine,dried (MgSO₄) and evaporated under reduced pressure to give the titlecompound as a yellow gum, 823 mg.

[0663]¹Hnmr (CDCl₃, 400 MHz) δ: 1.62 (m, 1H), 2.06 (m, 2H), 2.24 (m,4H), 2.56 (m, 1H), 2.62 (m, 1H), 2.94 (m, 1H), 3.58 (m, 4H), 4.44 (m,1H), 6.05 (bs, 1H), 7.20-7.35 (m, 5H).

[0664] LRMS: m/z (ES⁺) 281, 283 [MH⁺]

Preparation 50 N-[(3R)-1-Benzylpyrrolidinyl]-4-chlorobutanamide

[0665]

[0666] The title compound was obtained as a gum from(3R)-1-benzyl-3-pyrrolidinamine following the procedure described inpreparation 49.

[0667]¹Hnmr (CDCl₃, 400 MHz) δ: 1.62 (m, 1H), 2.10 (m, 2H), 2.232 (m,4H), 2.58 (m, 1H), 2.64 (m, 1H), 2.96 (m, 1H), 3.62 (m, 4H), 4.50 (m,1H), 6.02 (bs, 1H), 7.15-7.35 (m, 5H).

[0668] LRMS: m/z (TSP⁺) 281.1, 283.1 [MH⁺]

Preparation 51 1-[(3S)-1-Benzylpyrrolidinyl]-2-pyrrolidone

[0669]

[0670] The pyrrolidine from preparation 49 (825 mg, 3 mmol) was added toa mixture of sodium hydride (176 mg, 60% dispersion in mineral oil, 4.4mmol) in 1-methyl-2-pyrrolidine (10 ml), and the reaction stirred atroom temperature for 18 hours. Aqueous ammonium chloride was added toquench the reaction, then the mixture extracted with ethyl acetate. Thecombined organic solutions were washed with water (3×), brine (3×),dried (MgSO₄) and evaporated under reduced pressure. The residual gumwas purified by column chromatography on silica gel usingdichloromethane:methanol (95:5) as eluant, to afford the title compoundas a yellow oil, 250 mg.

[0671]¹Hnmr (CDCl₃, 400 MHz) δ: 1.70 (m, 1H), 1.94 (m, 2H), 2.10 (m,1H), 2.28 (m, 3H), 2.44 (m, 1H), 2.56 (m, 1H), 2.84 (m, 1H), 3.38-3.68(m, 4H), 4.76 (m, 1H), 7.20-7.35 (m, 5H).

[0672] LRMS: m/z (TSP⁺) 245.1 [MH⁺]

Preparation 52 1-[(3R)-1-Benzylpyrrolidinyl]-2-pyrrolidone

[0673]

[0674] The title compound was obtained as a yellow gum in 18% yield,from the compound from preparation 50, following the procedure describedin preparation 51.

[0675]¹Hnmr (CDCl₃, 400 MHz) δ: 1.74 (bs, 1H), 1.98 (m, 2H), 2.08 (m,1H), 2.16 (m, 3H), 2.50 (m, 1H), 2.62 (m, 1H), 2.90 (m, 1H), 3.40-3.75(m, 4H), 4.78 (s, 1H), 7.20-7.35 (m, 5H).

[0676] LRMS: m/z (TSP⁺) 245.2 [MH⁺]

Preparation 53 1-[(3S)-Pyrrolidinyl]-2-pyrrolidone

[0677]

[0678] A mixture of the protected pyrrolidine from preparation 51 (246mg, 1 mmol) and palladium hydroxide (150 mg) in ethanol (10 ml), washydrogenated at 60 psi and 60° C. for 18 hours. The cooled mixture wasfiltered through Arbocel®, washing through with ethanol, and thefiltrate evaporated under reduced pressure, to give the title compoundas a yellow gum, 156 mg.

[0679]¹Hnmr (CDCl₃, 400 MHz) δ: 1.86 (m, 1H), 1.97-2.17 (m, 3H), 2.38(t, 2H), 3.02 (m, 2H), 3.20 (m, 2H), 3.41 (m, 2H), 4.60 (m, 1H)4.70-4.92 (bs, 1H).

Preparation 54 1-[(3R)-pyrrolidin-3-yl]-2-pyrrolidone

[0680]

[0681] The title compound was obtained as a gum, from the protectedpyrrolidine from preparation 52, following the procedure described inpreparation 53.

[0682]¹Hnmr (CDCl₃, 400 MHz) δ: 1.78 (m, 1H), 2.05 (m, 3H), 2.38 (t,2H), 2.8-3.05 (m, 3H), 3.16 (m, 2H), 3.42 (t, 2H), 4.60 (m, 1H).

[0683] LRMS: m/z (TSP⁺) 155.2 [MH⁺]

Preparation 55 1-Benzyl-4-ethyl-4-piperidinol

[0684]

[0685] Ethylmagnesium bromide (18 ml, 3M solution in diethyl ether, 54mmol) was added dropwise over 30 minutes to a cooled (−78° C.) solutionof 1-benzyl-4-piperidinone (5 g, 26.4 mmol) in diethyl ether (50 ml).Once addition was complete, the mixture was allowed to warm to roomtemperature and then stirred for 18 hours.

[0686] The residual gum was purified by column chromatography on silicagel using an elution gradient of dichloromethane:methanol:0.88 ammonia(97:3:0.5 to 90:10:1) to afford the title compound as an oil, 848 mg.

[0687]¹Hnmr (CDCl₃, 400 MHz) δ: 0.94 (t, 3H), 1.52 m, 4H), 1.63 (m, 2H),2.35 (m, 2H), 2.62 (m, 2H), 3.55 (s, 2H), 7.32 (m, 5H).

Preparation 56 4-Ethyl-4-piperidinol

[0688]

[0689] A mixture of the amine from preparation 55 (848 mg, 3.87 mmol)and palladium hydroxide (300 mg) in ethanol (30 ml) was hydrogenated at60 psi and room temperature for 18 hours. The mixture was filteredthrough Arbocel®, and the filtrate evaporated under reduced pressure togive the title compound as an oil, 380 mg.

[0690]¹Hnmr (CDCl₃, 400 MHz) δ: 0.93 (t, 3H), 1.45-1.66 (m, 6H),2.88-3.04 (m, 4H).

Preparation 57 tert-Butyl4-hydroxy-4-(trifluoromethyl)-1-piperidinecarboxylate

[0691]

[0692] Tetrabutylammonium fluoride (50 mg, 1M solution intetrahydrofuran) was added to an ice-cooled solution of(trifluoromethyl)trimethylsilane (2.1 g, 15 mmol) and tert-butyl4-oxo-1-piperidinecarboxylate (2 g, 10 mmol) in tetrahydrofuran (20 ml),and the reaction stirred at room temperature for 18 hours. The mixturewas concentrated under reduced pressure, the residue suspended in ethylacetate, hydrochloric acid (20 ml, 1N) was added, the mixture stirredfor an hour, and then neutralised using sodium bicarbonate. The solutionwas washed with water, then brine, dried (MgSO₄) and evaporated underreduced pressure to give a gum. This was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 98:2) to afford the title compound,1.94 g.

[0693]¹Hnmr (CDCl₃, 400 MHz) δ: 1.42 (s, 9H), 1.68 (d, 2H), 1.76 (m,2H), 3.02 (m, 2H), 4.02 (m, 2H).

[0694] LRMS: m/z (TSP⁺) 270.2 [MH⁺]

Preparation 58 4-Trifluoromethylpiperidinol Trifluoroacetate

[0695]

[0696] A mixture of the piperidine from preparation 57 (950 mg, 3.6mmol) and trifluoroacetic acid (5 ml) in dichloromethane (5 ml) wasstirred at room temperature for 90 minutes. The mixture was concentratedunder reduced pressure, and the residue azeotroped with toluene anddichloromethane. The product was triturated with diethyl ether to affordthe title compound as a yellow solid, 866 mg.

[0697]¹Hnmr (CDCl₃, 400 MHz) δ: 1.94 (m, 4H), 3.18-3.35 (m, 4H).

[0698] LRMS: m/z (TSP⁺) 170.0 [MH⁺]

Preparation 59 tert-Butyl4-[acetyl(methyl)amino]-1-piperidinecarboxylate

[0699]

[0700] Triethylamine (18 ml, 132 mmol), followed by acetic anhydride(8.8 ml, 93 mmol) were added to a solution of tert-butyl4-[(methyl)amino]-1-piperidinecarboxylate (WO 9639385) (9 g, 89 mmol) indichloromethane (300 ml), and the reaction stirred at room temperaturefor 1 hour. The solution was diluted with dichloromethane (200 ml),washed with 2N citric acid (2×200 ml), brine, dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using dichloromethane:methanol(90:10), and the product azeotroped with dichloromethane to afford thetitle compound as a yellow oil, 20.5 g.

[0701]¹Hnmr (CDCl₃, 300 MHz) δ: (mixture of rotamers) 1.40-1.74 (m,13H), 2.09, 2.13 (2×s, 3H), 2.67-2.83 (m, 5H), 3.62, 4.60 (2×m, 1H),4.12-4.25 (m, 2H).

Preparation 60 N-methyl-N-(4-piperidinyl)acetamide Hydrochloride

[0702]

[0703] A solution of the protected amine from preparation 59 (20 g, 78mmol) in dichloromethane (200 ml) was saturated with hydrogen chloride,and the reaction then stirred at room temperature for 1 hour. Themixture was concentrated under reduced pressure, the residue azeotropedwith dichloromethane (3×300 ml), and the resulting solid triturated withdiethyl ether. The solid was filtered off, and dried under vacuum, togive the title compound as a white solid, 16.3 g.

[0704]¹Hnmr (DMSOd₆, 300 MHz) δ: (mixture of rotamers) 1.55 (m, 1H),1.70 (m, 1H), 1.96-2.15 (m, 5H), 2.60, 2.78 (2×s, 3H), 2.82-3.02 (m,2H), 3.22 (m, 2H), 3.98, 4.47 (2×m, 1H), 9.23-9.42 (bs, 2H).

Preparation 61 1-Benzyl-4-piperidinyl Methylcarbamate

[0705]

[0706] Methyl isocyanate (8.94 g, 157 mmol) was added to a solution of1-benzyl-4-piperidinol (10 g, 52.3 mmol) in chloroform (80 ml), and thereaction stirred under reflux for 16 hours. The cooled mixture wasconcentrated under reduced pressure, the residual solid was trituratedfrom 40-60 petroleum ether, and the product filtered and dried to affordthe title compound as a white solid, 1 g. m.p.—106-108° C.

[0707] Microanalysis found: C, 67.86; 8.14; N, 11.25. C₁₄H₂₀N₂O₂requires C, 67.71; H, 8.12;N, 11.28%.

Preparation 62 4-Piperidinyl Methylcarbamate

[0708]

[0709] A mixture of the piperidine from preparation 61 (8.2 g, 33.0mmol) and 10% palladium on charcoal (1 g) in ethanol (200 ml) washydrogenated at 50° C. and 50 psi for 18 hours. The cooled reaction wasfiltered through Hyflo®, and the filtrate evaporated under reducedpressure to afford the title compound as a white solid, 5.5 g.

[0710]¹Hnmr (CDCl₃, 90 MHz) δ: 1.0-2.10 (m, 4H), 2.30-3.30 (m, 7H),4.40-5.20 (m, 2H).

[0711] Microanalysis found: C, 53.29; H, 8.87; N, 17.78. C₇H₁₄N₂O₂requires C, 53.14; H, 8.91; N, 17.71%.

Preparation 63 tert-Butyl4-(4-hydroxypiperidin-1-yl)-1-piperidinecarboxylate

[0712]

[0713] Acetic acid (3.25 ml, 41.3 mmol) followed by tert-butyl4-oxo-1-piperidinecarboxylate (1 g, 5.0 mmol) and sodiumtriacetoxyborohydride (2.11 g, 10 mmol) were added to a solution of4-piperidinol (757 mg, 7.5 mmol) and triethylamine (5.5 ml, 37.5 mmol)in dichloromethane (50 ml), and the reaction stirred at room temperaturefor 18 hours. The reaction was washed with sodium bicarbonate solution,dried (MgSO₄) and evaporated under reduced pressure. The residual oilwas purified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 93:7:0.5)to give the title compound as a clear gum, 700 mg.

[0714]¹Hnmr (CDCl₃, 400 MHz) δ: 1.40 (m, 11H), 1.58 (m, 2H), 1.78 (m,2H), 1.95 (m, 2H), 2.24-2.48 (m, 3H), 2.68 (m, 2H), 2.82 (m, 2H), 3.70(m, 1H), 4.16 (m, 2H).

Preparation 64 1-(Piperidin-4-yl)-4-piperidinol Ditrifluoroacetate

[0715]

[0716] Trifluoroacetic acid (0.58 ml, 7.5 mmol) was added dropwise to anice-cooled solution of the amine from preparation 63 (700 mg, 2.5 mmol)in dichloromethane (10 ml), and the reaction stirred at room temperaturefor 18 hours. Tlc analysis showed starting material remaining, soadditional trifluoroacetic acid (0.97 ml, 12.5 mmol) was added, and thereaction stirred for a further 2 hours. The mixture was concentratedunder reduced pressure and the residue azeotroped with toluene to affordthe title compound as an oil, 1.25 g.

[0717]¹Hnmr (CD₃OD, 400 Hz) δ:1.97 (m, 4H), 2.17 (m, 1H), 2,37 (m, 3H),3.15 (m, 3H), 3.28-3.61 (m, 7H).

Preparation 65 4-(4-piperidinyl)morpholine Hydrochloride

[0718]

[0719] Hydrogen chloride was bubbled through an ice-cooled solution oftert-butyl 4-(4-morpholinyl)-1-piperidinecarboxylate (J.O.C. 1990;55(8); 2552) (6.5 g, 24 mmol) in dichloromethane (100 ml), and thesolution then stirred at 0° C. for 2 hours. The reaction was degassedunder nitrogen, allowed to warm to room temperature, and evaporatedunder reduced pressure to afford the title compound as a white solid,5.91 g.

[0720]¹Hnmr (DMSOd₆, 400 MHz) δ: 1.90 (m, 2H), 2.22 (m, 2H), 2.80 (m,2H), 3.00 (m, 2H), 3.38 (m, 5H), 3.90 (m, 4H), 8.92 (bs, 1H), 9.20 (bs,1H).

[0721] LRMS: m/z (ES⁺) 171.2 [MH⁺]

Preparation 66 3-(4-Pyridyl)-2,4-imidazolidinedione

[0722]

[0723] A mixture of 4-aminopyridine (25 g, 266 mmol) andethylisocyanoacetate (35 g, 271 mmol) in N,N-dimethylformamide (250 ml)was heated under reflux for 90 minutes, and allowed to cool. Theresulting precipitate was filtered off, and the filtrate heated underreflux for a further 5 hours. The cooled mixture was concentrated underreduced pressure, and the residue triturated with hot ethanol (500 ml).The resulting solid was filtered, and recrystallised fromN,N-dimethylformamide to afford the title compound as a yellowcrystalline solid, 47.8 g.

[0724] m.p. 232-234° C.

[0725] Microanalysis found: C, 53.98; H, 3.99; N, 23.63. C₈H₇N₃O₂requires C, 54.23; H, 3.98; N, 23.63%

Preparation 67 3-(4-Piperidinyl)-2,4-imidazolidinedione

[0726]

[0727] The pyridyl compound from preparation 66 (42 g, 0.24 mol) wasdissolved in 5N hydrochloric acid, then evaporated under reducedpressure. The solid was dissolved in water, 5% rhodium on alumina (15 g)added, and the mixture hydrogenated at 50° C. and 750 psi. The cooledmixture was filtered, the filtrate concentrated under reduced pressureand the residue dissolved in water. The solution was basified andevaporated under reduced pressure. The resulting solid was extractedinto ethyl acetate using a Soxhlet apparatus over 2 days. The organicsolution was evaporated under reduced pressure and the residual yellowsolid recrystallised from methanol/butanol to afford the title compoundas a white solid, 6.9 g.

[0728] m.p. 214-217° C.

[0729] Microanalysis found: C, 52.20; H, 7.21; N, 23.04. C₇H₁₂N₃O₂requires C, 52.44; H, 7.15; N, 22.94%

Preparation 68 tert-Butyl 4-(4-pyridinyl)-1-piperidinecarboxylate

[0730]

[0731] Dichloromethane (0.1 ml) was added to a suspension of zinc (2 g,31.7 mmol) in N,N-dimethylformamide (5 ml), and the mixture warmed untilgas evolution occurred. tert-Butyl 4-iodo-1-piperidinecarboxylate (EP1078928) (4.9 g, 15.8 mmol), and hydroquinone (35 mg, 0.32 mmol) inN,N-dimethylformamide (5 ml) was added, and the mixture warmed until anexotherm was evident. 4-Bromopyridine (1 g, 6.33 mmol),tris(dibenzylideneacetone)dipalladium (0) (73 mg, 0.127 mmol) andtri(2-furyl)phosphine (59 mg, 0.25 mmol) in N,N-dimethylformamide (5 ml)were added, and the reaction stirred at 60° C. for 30 minutes. Thecooled mixture was partitioned between water (100 ml) and diethyl ether(50 ml), and the layers separated. The aqueous phase was extracted withdiethyl ether (2×50 ml), the combined organic solutions washed withbrine (50 ml), dried (MgSO₄) and evaporated under reduced pressure, togive a brown oil. This was purified by column chromatography on silicagel using ethyl acetate:pentane (50:50) as eluant to afford the titlecompound as a yellow oil, 1.1 g.

[0732]¹Hnmr (CDCl₃, 400 MHz) δ: 1.43 (s, 9H), 1.58 (m, 2H), 1.80 (m,2H), 2.60 (m, 1H), 2.78 (m, 2H), 4.25 (m, 2H), 7.09 (d, 2H), 8.49 (d,2H).

[0733] LRMS: m/z (TSP⁺) 263.2 [MH⁺]

Preparation 69 tert-Butyl 4-(3-pyridinyl)-1-piperidinecarboxylate

[0734]

[0735] The title compound was obtained as an oil in 40% yield, fromtert-butyl 4-iodo-1-piperidinecarboxylate (EP 1078928) and3-bromopyridine, according to the procedure described in preparation 68.

[0736]¹Hnmr (CDCl₃, 400 MHz) δ: 1.42 (s, 9H), 1.58 (m, 2H), 1.78 (m,2H), 2.62 (m, 1H), 2.78 (m, 2H), 4.21 (m, 2H), 7.20 (m, 1H), 7.45 (d,1H), 8.42 (m, 2H).

[0737] LRMS: m/z (TSP⁺) 263.1 [MH⁺]

Preparation 70 tert-Butyl4-(1-oxido-4-pyridinyl)-1-piperidinecarboxylate

[0738]

[0739] Phthalic anhydride (1.41 g, 9.53 mmol) was added to a suspensionof urea hydrogen peroxide addition compound (2.87 g, 30.5 mmol) indichloromethane (10 ml), and the mixture stirred at room temperature for15 minutes. The pyridyl compound from preparation 68 (1 g, 3.82 mmol) indichloromethane (10 ml) was added and the reaction stirred at roomtemperature for 72 hours. The mixture was washed with water (100 ml),and the aqueous solution was extracted with further dichloromethane(3×75 ml). The combined organic solutions were washed with brine (75ml), dried (MgSO₄) and concentrated under reduced pressure. The residualoil was purified by column chromatography on silica gel usingdichloromethane:methanol (95:5) as eluant to afford the title compoundas an off-white oil, 978 mg.

[0740]¹Hnmr (CDCl₃, 400 MHz) δ: 1.46 (s, 9H), 1.58 (m, 2H), 1.82 (m,2H), 2.66 (m, 1H), 2.80 (m, 2H), 4.28 (m, 2H), 7.14 (d, 2H), 8.18 (d,2H).

[0741] LRMS: m/z (TSP⁺) 279.2 [MH⁺]

Preparation 71 tert-Butyl4-(1-oxido-3-pyridinyl)-1-piperidinecarboxylate

[0742]

[0743] The title compound was obtained as a white solid in 62% yieldfrom the pyridyl compound from preparation 69, according to theprocedure descibed in preparation 70.

[0744]¹Hnmr (CDCl₃, 400 MHz) δ: 1.46 (s, 9H), 1.58 (m, 2H), 1.82 (m,2H), 2.63 (m, 1H), 2.78 (m, 2H), 4.26 (m, 2H), 7.14 (d, 1H), 7.23 (d,1H), 8.11 (m, 2H).

[0745] LRMS: m/z (TSP⁺) 279.1 [MH⁺]

Preparation 72 4-(4-Piperidinyl)pyridine 1-oxide Hydrochloride

[0746]

[0747] Hydrogen chloride was bubbled through a solution of the pyridylcompound from preparation 70 (978 mg, 3.52 mmol) in dichloromethane (100ml) for 15 minutes. The reaction mixture was then evaporated underreduced pressure to afford the title compound as a white solid, 1.01 g.

[0748]¹Hnmr (CD₃OD, 400 MHz) δ: 2.00 (m, 2H), 2.18 (m, 2H), 3.18 (m,2H), 3.28 (m, 1H), 3.54 (m, 2H), 8.00 (d, 2H), 8.84 (d, 2H).

[0749] LRMS: m/z (TSP⁺) 179.2 [MH⁺]

Preparation 73 3-(4-Piperidinyl)pyridine 1-oxide Hydrochloride

[0750]

[0751] The title compound was obtained as a white solid in quantitativeyield, from the pyridyl compound from preparation 71, following theprocedure described in preparation 72.

[0752]¹Hnmr (CD₃OD, 400 MHz) δ: 2.00 (m, 2H), 2.18 (m, 2H), 3.18 (m,2H), 3.24 (m, 1H), 3.54 (m, 2H), 7.98 (dd, 1H), 8.32 (d, 1H), 8.78 (d,1H), 8.90 (s, 1H).

[0753] LRMS: m/z (TSP⁺) 179.2 [MH⁺]

Preparation 74 1-(1-Oxido-2-pyridinyl)piperazine Dihydrochloride

[0754]

[0755] A mixture of 2-chloropyridine 1-oxide (1 g, 6.06 mmol) andpiperazine hexahydrate (6 g, 30.9 mmol) were heated at 160-180° C. for 4hours, using a Dean and Stark apparatus. The cooled mixture was dilutedwith methanol (15 ml) and dichloromethane (100 ml), silica gel (12 g)added, and the mixture evaporated under reduced pressure. This waspurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (94:12:2) as eluant to give ayellow oil. This was suspended in ethereal hydrochloric acid, and themixture evaporated under reduced pressure to afford the title compoundas a white powder, 0.94 g.

[0756]¹Hnmr (DMSOd₆, 400 MHz) δ: 3.20 (m, 4H), 3.58 (m, 4H), 7.02 (dd,1H), 7.16 (d, 1H), 7.37 (dd, 1H), 8.18 (d, 1H), 9.42 (bs, 2H).

Preparation 75 tert-Butyl4-(3-cyano-2-pyridinyl)-1-piperazinecarboxylate

[0757]

[0758] A mixture of 2-chloro-3-cyanopyridine (15.2 g, 0.11 mol),tert-butyl 1-piperazinecarboxylate (25 g, 0.13 mol) and triethylamine(18 ml, 0.13 mol) in toluene (200 ml), was heated under reflux for 24hours. The cooled mixture was concentrated under reduced pressure andthe residue suspended in ethyl acetate (250 ml), and washed with water(3×). The organic solution was dried (MgSO₄), and concentrated underreduced pressure. The residue was triturated with pentane, filtered anddried in vacuo, at 60° C., to afford the title compound as a creamcoloured solid, 24.2 g.

[0759]¹Hnmr (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 3.59 (m, 4H), 3.66 (m,4H), 6.78 (dd, 1H), 7.78 (d, 1H), 8.35 (d, 1H).

[0760] LRMS: m/z (TSP⁺) 289.2 [MH⁺]

Preparation 76 tert-butyl4-[3-(aminomethyl)-2-pyridinyl]-1-piperazinecarboxylate

[0761]

[0762] A mixture of the nitrile from preparation 75 (708 mg, 2.45 mmol)and Raney Nickel® (170 mg) in ethanolic ammonia (20 ml) was hydrogenatedat 60 psi for 16 hours. The mixture was filtered through Arbocel®, andthe filtrate evaporated under reduced pressure to give the titlecompound as an oil.

[0763]¹Hnmr (CDCl₃, 400 MHz) δ: 1.43 (s, 9H), 3.07 (m, 4H), 3.53 (m,4H), 3.85 (bs, 2H), 6.95 (dd, 1H), 7.63 (d, 1H), 8.19 (s, 1H).

[0764] LRMS: m/z (TSP⁺) 292.43 [MH⁺]

Preparation 77 tert-Butyl4-[3-[(dimethylamino)methyl]-2-pyridinyl]-1-piperazinecarboxylate

[0765]

[0766] Formaldehyde (2 ml, 33% aqueous solution) and sodiumtriacetoxyborohydride (525.6 mg, 2.48 mmol) were added to a solution ofthe amine from preparation 76 (362.1 mg, 1.24 mmol) in dichloromethane(10 ml), and the solution stirred at room temperature for 45 minutes.The mixture was washed with saturated aqueous sodium bicarbonatesolution, brine, dried (MgSO₄) and evaporated under reduced pressure toafford the title compound as a yellow oil, 375 mg.

[0767]¹Hnmr (CDCl₃, 300 MHz) δ: 1.52 (s, 9H), 2.28 (s, 6H), 3.15 (m,4H), 3.41 (s, 2H), 3.59 (m, 4H), 6.97 (dd, 1H), 7.72 (d, 1H), 8.22 (d,1H).

[0768] LRMS: m/z (TSP⁺) 321.3 [MH⁺]

Preparation 78 tert-Butyl4-(3-{[(methylsulfonyl)amino]methyl}-2-pyridinyl)-1-piperazinecarboxylate

[0769]

[0770] Triethylamine (0.2 ml, 1.43 mmol), followed by methanesulfonylchloride (0.1 ml, 1.29 mmol) were added to an ice-cooled solution of theamine from preparation 76 (362.1 mg, 1.24 mmol) in dichloromethane (10ml), and the solution stirred for 30 minutes. The mixture was washedwith 10% aqueous citric acid solution, then brine, dried (MgSO₄) andevaporated under reduced pressure to afford the title compound as ayellow oil, 306 mg.

[0771]¹Hnmr (CDCl₃, 300 MHz) δ: 1.49 (s, 9H), 2.93 (s, 3H), 3.12 (s,4H), 3.61 (m, 4H), 4.39 (s, 2H), 5.51 (bs, 1H), 7.06 (dd, 1H), 7.69 (d,1H), 8.32 (s, 1H).

[0772] LRMS: m/z (TSP⁺) 371.2 [MH⁺]

Preparation 79 N,N-Dimethyl[2-(1-piperazinyl)-3-pyridinyl]methanamineTrihydrochloride

[0773]

[0774] Hydrogen chloride was bubbled through a solution of the protectedamine from preparation 77 (375.8 mg, 1.17 mmol) in dichloromethane (50ml), and the solution stirred for 30 nmiutes. The mixture was evaporatedunder reduced pressure and the residue dried in vacuo, to afford thetitle compound, 371 mg.

[0775]¹Hnmr (CD₃OD, 300 MHz) δ: 2.94 (s, 6H), 3.41-3.58 (m, 10H), 7.42(dd, 1H), 8.17 (d, 1H), 8.52 (d, 1H).

[0776] LRMS: m/z (TSP⁺) 221.2 [MH⁺]

Preparation 80N-Methyl-N-{[2-(1-piperazinyl)-3-pyridinyl]methyl}methanesulfonamideDihydrochloride

[0777]

[0778] The title compound was obtained as a white solid in 97% yieldfrom the protected amine from preparation 78, according to the proceduredescribed in preparation 79.

[0779]¹Hnmr (DMSOd₆, 300 MHz) δ: 2.94 (s, 3H), 3.18 (m, 4H), 3.31 (m,4H), 4.12 (s, 2H), 7.17 (dd, 1H), 7.59 (bs, 1H), 7.87 (d, 1H), 8.19 (d,1H), 9.33 (bs, 2H).

[0780] LRMS: m/z (TSP⁺) 271.2 [MH⁺]

Preparation 81 tert-Butyl 4-(methylsulfonyl)-1,4-diazepane-1-carboxylate

[0781]

[0782] Methanesulfonyl chloride (0.64 ml, 8.24 mmol) was added to asolution of tert-butyl 1,4-diazepane-1-carboxylate (1.5 g, 7.49 mmol)and triethylamine (1.6 ml, 11 mmol) in dichloromethane (20 ml), and thereaction stirred at room temperature for 18 hours. The solution waswashed with sodium bicarbonate solution, then brine, dried (MgSO₄) andevaporated under reduced pressure to give the title compound, 2.01 g.

[0783]¹Hnmr (CDCl₃, 300 MHz) δ: 1.45 (s, 9H), 1.95 (m, 2H), 2.83 (s,3H), 3.38 (m, 4H), 3.52 (m, 4H).

Preparation 82 1-(Methylsulfonyl)-1,4-diazepane Hydrochloride

[0784]

[0785] Hydrogen chloride was bubbled through an ice-cooled solution ofthe compound from preparation 81 (2.0 g, 7.2 mmol) in dichloromethane(50 ml), for 15 minutes. The solution was allowed to warm to roomtemperature and concentrated under reduced pressure. The residue wasazeotroped with dichloromethane and triturated with diethyl ether toafford the title compound as a solid, 1.45 g.

[0786]¹Hnmr (DMSOd₆, 300 MHz) δ: 2.00 (m, 2H), 2.98 (s, 3H), 3.17 (m,4H), 3.35 (t, 2H), 3.54 (t, 2H), 9.35 (bs, 2H).

[0787] LRMS: m/z (TSP⁺) 179.2 [MH⁺]

Preparation 83N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxopiperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide

[0788]

[0789] Triethylamine (4.2 ml, 30 mmol) was added to a suspension of[(3S)-3-(3,4-dichlorophenyl)-6-oxopiperidinyl]acetaldehyde (WO 9605193)(5 g, 17.5 mmol) and the amine from preparation 60 (5 g, 26.2 mmol) indichloromethane (400 ml) and the mixture stirred at room temperature,until all solids had dissolved. Acetic acid, was added (ca. 5 ml) to thereaction to give pH 4, the solution stirred for 30 minutes, then sodiumtriacetoxyborohydride (7.4 g, 35 mmol) added, and the reaction stirredfor 3 hours. The mixture was diluted with dichloromethane (300 ml), andwashed with sodium hydroxide solution (400 ml, 1N). The aqueous phasewas extracted with further dichloromethane (×2), the combined organicsolutions washed with brine, dried (Na₂SO₄) and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using an elution gradient of dichloromethane:methanol:0.88ammonia (99:1:0.1 to 85:15:1.5) to give the title compound, 4.5 g.

[0790]¹Hnmr (CD₃OD, 400 MHz) δ: 1.35-2.17 (m, 15H), 2.17-2.41 (m, 3H),2.75 (m, 1H), 2.78-2.93 (m, 4H), 3.40 (dd, 1H), 3.75 (dd, 1H), 3.56,4.25 (m, 1H), 7.33 (m, 1H), 7.49 (d, 1H), 7.56 (s, 1H).

[0791] LRMS: m/z (ES⁺) 448, 450 [MNa⁺]

Preparation 84 tert-Butyl1-(1-{2-[(3S)-3-(3,4-dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-3-azetidinyl)-4-piperidinylcarbamate

[0792]

[0793] A mixture of the aldehyde from preparation 11a (250 mg, 0.62mmol), tert-butyl-1-(3-azetidinyl)-4-piperidinylcarbamatetrifluoroacetate (WO 9605193) (450 mg, 0.93 mmol), triethylamine (1 ml)and acetic acid (1.1 ml) and sodium triacetoxyborohydride (250 mg, 1.24mmol) in dichloromethane (50 ml) was stirred at room temperature for 90minutes. The reaction mixture was washed with water, dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 95:5) to afford the title compound,252 mg.

[0794]¹Hnmr (CDCl₃, 400 MHz) δ: 1.44 (s, 9H), 1.82-2.70 (m, 16H),2.80-3.05 (m, 3H), 3.48 (m, 1H), 3.62 (m, 2H), 3.92 (d, 1H), 4.40 (d,1H), 4.58 (d, 1H), 7.18 (m, 1H), 7.22 (d, 1H), 7.42 (s, 1H), 7.44 (d,1H), 7.74 (d, 2H), 8.54 (d, 1H).

[0795] LRMS: m/z (TSP⁺) 502.1, 503.1 [MH⁺]

Preparation 85 tert-Butyl1-(1-{2-[(3S)-3-(3,4-dichlorophenyl)-1-(6-methyl-2-pyridinyl)-6-oxopiperidinyl]ethyl}-3-azetidinyl)-4-piperidinylcarbamate

[0796]

[0797] A mixture of the aldehyde from preparation 12a (260 mg, 0.71mmol), tert-butyl-1-(3-azetidinyl)-4-piperidinylcarbamatetrifluoroacetate (WO 9605193) (350 mg, 0.78 mmol), triethylamine (0.26ml, 1.86 mmol) and titanium isopropoxide (2.3 ml, 0.78 mmol) in ethanol(3 ml), was stirred at room temperature for 18 hours. Sodium borohydride(50 mg, 1.35 mmol) in ethanol (5 ml) was then added and the reactionstirred for 30 minutes. Sodium hydroxide was added, the resultingprecipitate filtered off, and washed with ethyl acetate. The filtratewas washed with water (2×) and brine (2×), dried (MgSO₄) and evaporatedunder reduced pressure. The residual gum was purified by columnchromatography on silica gel using an elution gradient ofdichloromethane:methanol (100:0 to 99:1) to afford the title compound asa yellow/white solid, 59 mg.

[0798]¹Hnmr (CDCl₃, 400 MHz) δ: 1.35 (m, 3H), 1.40 (s, 9H), 1.64-1.95(m, 8H), 2.08 (m, 2H), 2.22 (m, 2H), 2.55 (m, 7H), 2.80 (t, 1H), 3.40(m, 2H), 3.80 (d, 1H), 4.36 (m, 1H), 4.44 (d, 1H), 6.96 (d, 1H), 7.16(d, 1H), 7.38 (dd, 2H), 7.50 (d, 1H), 7.58 (dd, 1H).

[0799] LRMS: m/z (TSP⁺) 617.2 [MH⁺]

1. A compound of formula (I):

or a pharmaceutically acceptable salt, prodrug, solvate or polymorphthereof, wherein: R is het^(a); R¹ is phenyl optionally substituted byone or more substituents independently selected from halogen, C₁₋₆alkoxy optionally substituted by one or more halogen, and C₁₋₆ alkyloptionally substituted by one or more halogen; m is 1-4; Z is selectedfrom: a) N(R³)(R⁴X) wherein X is NR³R⁵, OR³, Oaryl¹, Ohet^(b), Ohet^(c),aryl¹, het^(b) or het^(c); c) N(R³)Y wherein Y is aryl¹, het^(b) orhet^(c); and c) a 4-7 membered N containing saturated or partiallysaturated heterocycle said heterocycle attached to the alkylene link viasaid nitrogen atom, said heterocycle optionally containing an additional1-3 groups, each independently selected from C═O, NH, S(O)_(p) and O;optionally, said heterocycle is: (i) spirofused with het^(b), such thatboth rings share 1 atom; or (ii) substituted by 1-3 groups eachindependently selected from het^(b), het^(c), aryl¹, R³, R⁴OR³,R⁴C(O)R³, OR³, OR⁷OR³, OR⁴OC(O)R³, OR⁴OC(O)NR³R⁶, S(O)_(p)R⁴, C(O)R³,C(O)NR³R⁶, C(O)OR³, R⁷C(O)OR³, C(O)R⁷OR³, C(O)OR⁷OR³, CF₃, NR³R⁶,R⁴NR³R⁵, OC(O)NR³R⁴ and NR³R⁵; wherein R³ and R⁶ are both independentlyselected from H and C₁₋₆alkyl; wherein R⁴ and R⁷ are both independentlyselected from C₁₋₆ alkylene; wherein R⁵ is selected from C(O)OR³,S(O)_(p)R³, S(O)_(p)aryl¹, C(O)R³, and C(O)NR³R⁶; het^(b) is a 4-7membered heterocycle containing 1-3 heteroatoms, each independentlyselected from N, O and S, said N being optionally substituted with O,said ring optionally containing 1-2 C═O groups, said ring beingsaturated or partially saturated, said ring being optionally benzofused,said ring being optionally substituted by 1-3 substituents selected fromhalo, R³, OR³, C(O)NR³R⁶, R⁷NR³R⁶, NR³R⁵, NHS(O)_(p)R⁴, S(O)_(p)NR³R⁶,S(O)_(p)R⁴, CN, NR³R⁶ and aryl¹; het^(a) and het^(c) independentlyrepresent a 5-7 membered aromatic heterocycle containing 1-3 heteroatomseach independently selected from N, O and S, said ring being optionallybenzofused, said ring system as a whole being optionally substituted by1-3 substituents, each independently selected from: halo, R³, OR³,C(O)NR³R⁶, R⁴NR³R⁶, NR³R⁵, NHS(O)_(p)R⁴, S(O)_(p)NR³R⁶, S(O)_(p)R, CN,NR³R⁶ and R⁴NR³S(O)_(p)R³; aryl¹ is phenyl or naphthyl, each optionallysubstituted by 1-3 substituents, each independently selected from: halo,R³, OR³, C(O)NR³R⁶, R⁷NR³R⁶, NR³R⁵, NHS(O)_(p)R⁴, S(O)_(p)NR³R⁶,S(O)_(p)R⁴, CN; p is 0, 1 or 2; and n is 0-4.
 2. A compound according toclaim 1 having the following stereochemistry:


3. A compound according to claim 1 or claim 2, wherein R is pyridyl,optionally substituted by NR³R⁶, R³ or OR³.
 4. A compound according toany of claims 1 to 3, wherein R¹ is phenyl optionally substituted by 1or 2 halo substituents.
 5. A compound according to any of claims 1 to 4,wherein m is 2-3.
 6. A compound according to any of claims 1 to 5,wherein n is 1-4.
 7. A compound according to any of claims 1 to 6,wherein R³ is H or C₁₋₄ alkyl.
 8. A compound according to any of claims1 to 7, wherein R⁴ is C₁₋₄ alkylene.
 9. A compound according to any ofclaims 1 to 8, wherein R⁵ is C(O)OR³, C(O)R³, C(O)NR³R⁶.
 10. A compoundaccording to any of claims 1 to 9, wherein Z is a piperidine orazetidine group optionally substituted by one or more of het^(b),het^(c), aryl¹, OR³, R³ and NR³R⁵, wherein; het^(b) is a 5-6 memberedsaturated or partially saturated nitrogen containing heterocycle, saidheterocycle optionally incorporating 1-2 groups each independentlyselected from O, C═O and N, said heterocycle being optionallybenzofused, said heterocycle being optionally substituted by 1-2substituents, each independently selected from OR³, R³, NR³R⁶, NR³R⁵,aryl¹, SO₂R⁴ and SO₂NR³R⁶; het^(c) is pyridyl, optionally substituted by1 or 2 substituents each independently selected from halo and OR³; aryl¹is phenyl, optionally substituted by 1 or 2 substituents eachindependently selected from halo and OR³; and R³, R⁴, R⁵ and R⁶ are asdefined in the previous claims.
 11. A compound according to any ofclaims 1 to 10, wherein Z is a piperidine or azetidine group, optionallysubstituted by het^(b), aryl¹ and NR³R⁵; wherein het^(b) is a morpholineor piperidine, optionally substituted at the 4 position by OH and ormethyl; wherein; aryl¹ is phenyl optionally substituted by OH; and R³ isH or methyl and R⁵ is C(O)CH₃
 12. A compound according to any of claims1 to 11, wherein Z is


13. A compound according to any of claims 1 to 10 selected from:(5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 131)(5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-hydroxypiperidinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 135a)(5S)-5-(3,4-Dichlorophenyl)-5-[2-(4-methoxy-1-piperidinyl)ethyl]-1-(2-pyridinyl)-2-piperidinone(Example 61)(5S)-5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{{2-[4-hydroxy-4-phenyl]-1-piperidinyl}ethyl}-2-piperidinone(Example 134)(5S)-5-(3,4-Dichlorophenyl)-5-{2-[4-hydroxy-4-(2-pyridyl)-1-piperidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone(Example 92)N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-phenyl-4-piperidinyl)-acetamide(Example 90)(5S)-5-(3,4-Dichlorophenyl)-1-(6-methoxy-2-pyridinyl)-5-{2-[3-(4-morpholinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 119)5-(3,4-Dichlorophenyl)-1-(6-methyl-2-pyridinyl)-5-{2-[3-(4-oxo-1-piperidinyl)-1-azetidinyl]ethyl}-2-piperidinone(Example 168)(5S)-5-(3,4-Dichlorophenyl)-5-{2-[3-(4-hydroxy-1-piperidinyl)-1-azetidinyl]ethyl}-1-(2-pyridinyl)-2-piperidinone(Example 73)N-(1-{2-[(3S)-3-(3,4-Dichlorophenyl)-6-oxo-1-(2-pyridinyl)piperidinyl]ethyl}-4-piperidinyl)-N-methylacetamide(Example 158)
 14. A process of preparing a compound according to any ofclaims 1 to 13 comprising subjecting a compound of formula (II) to areductive amination to give a compound of formula (I):

wherein R, R¹, m, n and Z are as defined in the previous claims.
 15. Aprocess for preparing a compound according to any of claims 1 to 13,comprising subjecting a compound (VIII) to an alkylation reaction togive a compound of formula (I):

wherein R, R¹, m, n and Z are as defined in the previous claims.
 16. Useof a compound according to any of claims 1 to 13, as a medicament. 17.Use of a compound according to any of claims 1 to 13, in the preparationof a medicament for the treatment of a condition selected from:inflammatory disease, a central nervous system (CNS) disorder, agastrointestinal (GI) disorder, a disease caused by Helicobacter pylorior other urease positive Gram negative bacteria, urological conditions,a pulmonary disorder, an allergy, a hypersensitivity disorder, avasospastic disease, a proliferative disorder, a fibrosing or collagendisease, reflux sympathetic dystrophy, an addiction disorder, astress-related somatic disorder, a peripheral neuropathy, aneuropathological disorder, a disorder related to immune enhancement orsuppression, a rheumatic disease, an opthalmic disease, acute andchronic pain or a viral disease.
 18. Use of a compound according to anyof claims 1 to 13 in the preparation of a medicament for the treatmentof a condition selected from: urological conditions or acute and chronicpain.
 19. A use according to claim 18, wherein said urological conditionis overactive bladder.
 20. A use according to claim 18, wherein saidpain is neuropathic pain.
 21. A method of treating or preventing acondition for which an NK₂ antagonist is efficacious which comprisesadministering a therapeutically effective amount of a compound accordingto any of claims 1 to 13 to a patient in need of treatment.
 22. Use of acompound according to any of claims 1 to 13 in the preparation of amedicament in combination with an agent selected from: muscarinicantagonists; alpha-adrenoceptor antagonists; serotonin/noradrenalinreuptake inhibitors (SNRI); noradrenalin reuptake inhibitors; NK₁antagonists; 5-HT_(1A) agonists/antagonists; PDE₅ inhibitors; COX₂inhibitors; non-selective COX inhibitors; vanilloid receptor agonists;HMG-COA reductase inhibitors; and estrogenic modulators and selectiveestrogen receptor modulators for the treatment of urological conditions.23. Use of a compound according to any of claims 1 to 13 in thepreparation of a medicament in combination with an agent selected from:NSAIDs, opioids, muscarinic antagonists; cholinergic analgesics;alpha-adrenoceptor antagonists; serotonin/noradrenalin reuptakeinhibitors (SNRI); COX₂ inhibitors; non-selective COX inhibitors;tricyclic antidepressants, anticonvulsants, serotonin reuptakeinhibitors, serotonin receptor agonists and antagonists, sedatives,skeletal muscle relaxant and NMDA receptor antagonists for the treatmentof pain.
 24. A composition comprising a compound according to any ofclaims 1 to 13 and a pharmaceutically acceptable diluent or carrier. 25.A composition comprising a compound according to any of claims 1 to 13and an agent selected from: Muscarinic antagonists; alpha-adrenoceptorantagonists; serotonin/noradrenalin reuptake inhibitors (SNRI); reuptakeinhibitors; NK, antagonists; 5-HT_(1A) agonists/antagonists; PDE₅inhibitors; COX₂ inhibitors; non-selective COX inhibitors (preferablywith ‘GI protection’); vanilloid receptor agonists; HMG-CoA reductaseinhibitors; estrogenic modulators and selective estrogen receptormodulators, and a pharmaceutically acceptable diluent or carrier.
 26. Acomposition comprising a compound according to any of claims 1 to 13 andan agent selected from: NSAIDs, opioids, muscarinic antagonists;cholinergic analgesics; alpha-adrenoceptor antagonists;serotonin/noradrenalin reuptake inhibitors (SNRI); COX₂ inhibitors;non-selective COX inhibitors; tricyclic antidepressants,anticonvulsants, serotonin reuptake inhibitors, serotonin receptoragonists and antagonists, sedatives, skeletal muscle relaxant and NMDAreceptor antagonists, and a pharmaceutically acceptable diluent orcarrier.
 27. A kit comprising a) a composition comprising a compoundaccording to any of claims 1 to 13 and a pharmaceutically acceptablediluent or carrier; b) a composition comprising an agent selected from:compounds which modulate the action of atrial natriuretic factor (alsoknown as atrial natriuretic peptide), such as inhibitors of neutralendopeptidase; compounds which inhibit angiotensin-converting enzyme,and combined inhibitors of angiotensin-converting enzyme and neutralendopeptidase; angiotensin receptor antagonists; substrates forNO-synthase; calcium-channel blockers; antagonists of endothelinreceptors and inhibitors of endothelin-converting enzyme; cholesterollowering agents; antiplatelet and antithrombotic agents, thromboplastinactivating factor inhibitors; insulin sensitising agents andhypoglycaemic agents; acetylcholinesterase inhibitors; non-steroidalanti-inflammatory agents (NSAIDs); cGMP PDE₅ inhibitors; muscarinicantagonists; alpha-adrenoceptor antagonists; serotonin/noradrenalinreuptake inhibitors (SNRI); noradrenalin reuptake inhibitors; NK₁antagonists; 5-HT_(1A) agonists/antagonists; COX₂ inhibitors;non-selective COX inhibitors (preferably with ‘GI protection’); opioids;tricyclic antidepressants; anticonvulsants, serotonin reuptakeinhibitors; serotonin receptor agonists and antagonists, cholinergic(muscarinic and nicotinic) analgesics, sedatives, skeletal musclerelaxants; NMDA receptor antagonists; vanilloid receptor agonists;HMG-CoA reductase inhibitors; estrogenic modulators and selectiveestrogen receptor modulators, and a pharmaceutically acceptable diluentor carrier; and c) a container.
 28. A kit comprising: a) a compositioncomprising a compound according to any of claims 1 to 13 and apharmaceutically acceptable diluent or carrier; and b) a compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt, solvate or prodrug thereof and an agent selected from: muscarinicantagonists; alpha-adrenoceptor antagonists; serotonin/noradrenalinreuptake inhibitors (SNRI); reuptake inhibitors; NK, antagonists;5-HT_(1A) agonists/antagonists; PDE₅ inhibitors; COX₂ inhibitors;non-selective COX inhibitors (preferably with ‘GI protection’);vanilloid receptor agonists; HMG-COA reductase inhibitors; estrogenicmodulators and selective estrogen receptor modulators, and apharmaceutically acceptable diluent or carrier; and c) a container. 29.A kit comprising: a) a composition comprising a compound according toany of claims 1 to 13 and a pharmaceutically acceptable diluent orcarrier; and b) a composition comprising a compound according to any ofclaims 1 to 13 and an agent selected from: NSAIDs, opioids, muscarinicantagonists; cholinergic analgesics; alpha-adrenoceptor antagonists;serotonin/noradrenalin reuptake inhibitors (SNRI); COX₂ inhibitors;non-selective COX inhibitors; tricyclic antidepressants,anticonvulsants, serotonin reuptake inhibitors, serotonin receptoragonists and antagonists, sedatives, skeletal muscle relaxant and NMDAreceptor antagonists, and a pharmaceutically acceptable diluent orcarrier; and c) a container.